Synthesis of cantharidin

ABSTRACT

The invention provides synthetic methods for the preparation of cantharidin and analogs thereof. In one aspect, the invention provides an improved Diels-Alder cycloaddition to generate a key intermediate en route to cantharidin and analogs thereof. In yet another aspect, the invention describes a new palladium-mediated carbonylation providing another key intermediate en route to cantharidin and analogs thereof. In addition to synthetic methods, present invention also provides compounds (i.e., intermediates) useful in the synthesis of cantharidin and analogs thereof. Compounds provided herein may have biological activity, and therefore may be used in the treatment of diseases or conditions (e.g., infectious diseases and skin conditions).

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application, U.S. Ser. No. 62/568,004, filed Oct. 4, 2017,the entire contents of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Cantharidin (1,2-dimethyl-3,6-epoxyperhydrophthalic anhydride) is alipophilic compound traditionally obtained from blister beetles,primarily of the family Meloidae. Cantharidin is an inhibitor of proteinphosphatase 2A and has vesicant activity when applied to the skin. Dueto its bioactivity, cantharidin is used in the treatment of various skinconditions, including the treatment of common warts and molluscum.Chemical names of cantharidin include(3aR,4S,7R,7aS)-3a,7a-dimethylhexahydro-4,7-epoxyisobenzofuran-1,3-dioneand 1,2-dimethyl-3,6-epoxyperhydrophthalic anhydride. Common namesinclude cantharidin, cantharone, cantharidine, and kantaridin. Thestructure of cantharidin is shown below:

The chemical synthesis of cantharidin has proven to be challenging.Early reported syntheses are lengthy and low yielding processes, involvepotentially dangerous operating conditions, and may be commerciallyimpractical. Some cantharidin syntheses have fewer steps and improvedyields but may require the use of extreme reaction conditions ordangerous reagents. Von Bruchhausen attempted the synthesis of thecantharidin in 1928. See, e.g., von Bruchhausen, F.; Bersch, II. W.Arch. Pharm. Ber. Disch. Phurm. Ges. 1928, 266, 697-702, which isincorporated herein by reference. His synthetic approach was based onthe following retrosynthetic analysis.

Unfortunately, the Diels-Alder reaction between the two reactantsresults in an equilibrium that is unfavorable with respect to thedesired product. As demonstrated in the following experiment, whennatural cantharidin is dehydrogenated, it spontaneously undergoes aretro Diels-Alder reaction. Studies have shown that the instability ofthe Diels-Alder product is due to the repulsion between the methylgroups at C₁ and C₂, and the repulsion between those methyl groups andthe endo hydrogens at C₃ and C₆.

Stork published a synthesis of cantharidin in 1951 which is noteconomically viable. See, e.g., Stork, G.; et al. J. Am. Chem. Soc.1951, 73, 4501; and Stork, G.; van Tamelen, E. E.; Friedman, L. I.;Burgstahler, A. W. J. Am. Chem. Soc. 1953, 75, 384; both of which areincorporated herein by reference. It is a lengthy, linear, multistep,and low-yielding process. On a large scale, this process requires theuse of dangerous reagents that are both expensive and have the potentialto create worker injury as well as unacceptable environmental disposalissues.

In 1953, Schenck published a Diels-Alder-based approach to cantharidin.See, e.g., Schenck, G.; Wirtz, R. Naturwissenshaften 1953, 40, 531,which is incorporated herein by reference. However, it still suffersfrom many of the issues noted above including being a long,low-yielding, linear, and multistep synthesis. Its use on amanufacturing scale may require large-scale use of toxic bromine anddisposal of an environmentally noxious brominated by-product wastestream.

In 1976, Dauben began the exploration of extreme high-pressureconditions to synthesize cantharidin. See, e.g., Dauben, W. G.; Kessel,C. R.; Takemura, K. H. J. Am. Chem. Soc. 1980, 102, 6893-6894; andDauben, W. G.; Krabbenhoft, II. O. J. Am. Chem. Soc. 1976, 98,1992-1993; both of which are incorporated herein by reference. Thissynthesis requires fewer steps to prepare cantharidin in good yield, butthe extreme pressures of 4-15 kilobar (kbar) necessary for theDiels-Alder step may be dangerous at commercial scale of production. Ifdone in multiple small batches, the process may be economicallyunattractive. This step may also require a significant capitalinvestment in exotic hydraulic high-pressure production equipment aswell as protective containment housing to ensure worker and communitysafety. Dauben's process is shown in the schemes below.

In 1990, Grieco demonstrated that the addition of 5 molar (M) lithiumperchlorate in diethyl ether can facilitate the Diels-Alder reactionreported by Dauben at ambient temperatures and pressures rather than atthe extreme pressures described above. See, e.g., Grieco, P. A. et al.J. Am. Chem. Soc. 1990, 112, 4595-4596, which is incorporated herein byreference. Unfortunately, lithium perchlorate is a high energy oxidizingagent that may form detonation-sensitive or highly explosive mixtureswhen combined with organic materials or metals. This includes standardreagents (Sodium), and standard plant materials (stainless steel).Accordingly, use of this procedure would significantly affect theequipment required to run this process, for instance, an entirelyglass-lined reactor system, including all piping and valves. Inaddition, diethyl ether is a highly volatile and flammable solvent. Thisreaction mixture of a high energy oxidizing agent with an easily ignitedsolvent may be dangerous even under controlled and small-scaleconditions. Additionally, perchlorate ion may be considered asignificant environmental pollutant especially when released into groundwater. Perchlorate may display adverse human health effects particularlytargeting iodine metabolism in the thyroid. This combination of serioussafety and environmental impact issues for this synthesis makes its useas a process for the commercial production of cantharidin untenable.However, the basic outline of this process for a commercial processusing this short synthetic strategy remains attractive. Grieco's processis outlined in the following scheme.

In a subsequent study by Handy in 1995, it was demonstrated that lithiumtrifluoromethanesulfonimide in diethyl ether or acetone also gave a goodyield of Diels-Alder adduct. See, e.g., Handy, S. T.; Grieco, P. A.;Mineur, C.; Ghosez, L. Synlett 1995, 565-567, which is incorporatedherein by reference. Unfortunately, this variant displays significanterosion in the exo-endo Diels-Alder product ratio. The exo-endo productsmay be difficult to separate resulting in significant losses of thedesired product required for subsequent transformation to cantharidin.Such losses so late in the synthesis may adversely impact the costs ofproduction and the ultimate profitability of the drug. Plus, the controlof the increased amount of endo byproduct in the production stream mayadd to the regulatory and quality control burden of production as wellas waste disposal costs.

Some recent developments useful in the synthesis of cantharidin andanalogs thereof have been described in, e.g., International PublicationNo. WO 2016/100732, published Jun. 23, 2016, the entire contents ofwhich is incorporated herein by reference.

Despite these advances in cantharidin synthesis, new methods useful inthe synthesis of cantharidin and analogs thereof are needed. Preferablythese methods involve mild conditions that can be used to produce on acommercial scale cantharidin, continued improvements in yield andselectivity and cantharidin analogs and derivatives that may bebiologically active.

SUMMARY OF THE INVENTION

This invention relates in part to improved methods for preparingcantharidin and analogs thereof. For instance, it has been discoveredthat the Diels-Alder reaction of Compound (2) with furan can be carriedout in the absence of increased pressure and/or in the absence of addedacid (e.g., Lewis acid) to yield Compound (1) (see Scheme 1).

This advancement eliminates many of the disadvantages associated withprevious cantharidin syntheses, including the high pressure and/or Lewisacids typically required for the key Diels-Alder step. For example, incertain embodiments, Compound (1) is formed by reacting Compound (2)with furan at atmospheric pressure, in the absence of a Lewis acid. Incertain embodiments, Compound (1) is formed by reacting Compound (2)with furan at atmospheric pressure, in the absence of a Lewis acid, in apolar solvent (e.g., a polar aprotic solvent, e.g., NMP). In certainembodiments, Compound (1) is formed by reacting Compound (2) with furanat atmospheric pressure, in the absence of a Lewis acid, in a polarsolvent (e.g., NMP), at a temperature above room temperature (e.g., from40-50° C.). As discussed herein, the product of the Diels-Alderreaction, Compound (1), is useful as a key intermediate in the synthesisof cantharidin and analogs thereof.

As discussed above, provided herein are methods of preparing Compound(1):

the methods comprising reacting Compound (2):

in the presence of furan; wherein the reaction is carried out in theabsence of an acid (i.e., in the absence of a Lewis acid or Brønstedacid) and in the absence of increased pressure (e.g., at approximatelyatmospheric pressure). In certain embodiments, the reaction is carriedout in the absence of a Lewis acid. In certain embodiments, the reactionis carried out in the absence of a Brønsted acid).

In certain embodiments, the Diels-Alder reaction is carried out in asolvent. In certain embodiments, the solvent is a polar solvent. Incertain embodiments, the Diels-Alder reaction is carried out in anaprotic polar solvent (e.g., acetone, ethyl acetate, furan,acetonitrile, N-Methyl-2-pyrrolidone (NMP), dimethyl formamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, sufolane, dimethylsulfone).In certain embodiments, the reaction is carried out at room temperatureor above (e.g., between room temperature and 100° C., e.g., at 40-50°C.). In certain embodiments, the reaction is carried out in the absenceof increased pressure (e.g., at approximately atmospheric pressure). Incertain embodiments, the reaction is carried out in an aprotic polarsolvent (e.g., NMP) with slight heating (e.g., at a temperature betweenroom temperature and 100° C., e.g., at around 45° C.), and atatmospheric pressure (i.e., at approximately 1 atm).

Also provided herein are methods of preparing a compound of Formula (I),which is useful as an intermediate in the synthesis of cantharidin andanalogs thereof. The method of preparing a compound of Formula (I)involves a new palladium-mediated carbonylation of a compound of Formula(II), as shown in Scheme 2.

As shown in Scheme 2, provided herein are methods of preparing acompound of Formula (I):

the methods comprising reacting a compound of Formula (II):

in the presence of palladium, carbon monoxide, and an alcohol of theformula R²OH;

-   wherein:

X¹ is halogen, optionally substituted sulfonate, or optionallysubstituted phosphate;

R¹ and R² are independently optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, or anoxygen protecting group.

The methods provided herein can be applied to the synthesis ofcantharidin, for example, as shown in Scheme 3. After the Diels-Alderreaction, Compound (1) can be hydrogenated and reduced to formcantharidin (Scheme 3). In certain embodiments, the hydrogenation andreduction are carried out in the same step.

The present invention provides further methods useful in the preparationof cantharidin and analogs thereof. For example, alternative routes tocantharidin provided herein are outlined in Scheme 5. These routes alsoinvolve a new Diels-Alder reaction; in particular, a Diels-Alderreaction between a compound of Formula (III) and furan to yield acycloadduct of Formula (IV). In certain embodiments, the Diels-Alderreaction is carried out in the absence of added acid (e.g., Lewis acid)and without the aid of increased pressure (i.e., at around atmosphericpressure). Compounds of Formula (IV) can then be hydrogenated,desulfurized, and hydrolyzed/dehydrated, in any order, to yieldcantharidin.

The present invention also provides compounds useful in the synthesis ofcantharidin and analogs thereof (e.g., compounds of Formula (I), (II),(III), (IV), (V), and (VI)).

Synthetic intermediates provided herein may also have promisingbiological activity. Therefore, provided herein are pharmaceuticalcompositions comprising a compound of Formula (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. Also provided herein are methods for treating adisease or condition (e.g., an infectious disease or skin condition) ina subject comprising administering to the subject a compound of Formula(IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof. Also provided herein are uses ofcompounds of Formulas (IV), (V), and (VI), and pharmaceuticallyacceptable salts thereof, and pharmaceutical composition thereof, forthe manufacture of medicaments for treating diseases or conditions(e.g., infectious diseases or skin conditions). In yet another aspect,the present invention provides kits comprising compounds orpharmaceutical compositions described herein.

The details of certain embodiments of the invention are set forth in theDetailed Description of Certain Embodiments, as described below. Otherfeatures, objects, and advantages of the invention will be apparent fromthe Definitions, Examples, and Claims.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The present invention provides synthetic methods and intermediatesuseful in the synthesis of cantharidin and analogs thereof. In oneaspect, the present invention provides methods for the synthesis ofCompound (1) using a Diels-Alder reaction between Compound (2) andfuran. With respect to this reaction, the present invention providesimproved conditions that provide for a safer, scalable, and/or moreeconomical synthesis of Compound (1). In another aspect, the presentinvention provides methods for the preparation of compounds of Formula(I) based on a palladium-mediated carbonylation of compounds of Formula(II). Compounds of Formula (I) are useful as intermediates in thepreparation cantharidin and analogs thereof. In yet another aspect, thepresent invention provides compounds/intermediates useful in thesynthesis of cantharidin and analogs thereof.

Synthetic intermediates provided herein may also have promisingbiological activity, e.g., as anti-infective agents, or as agents totreat a variety of skin conditions. Therefore, provided herein arepharmaceutical compositions, methods, uses, and kits for treating adiseases or conditions.

Methods of Preparing Compound (1)

Provided herein are methods of preparing Compound (1):

the method comprising reacting Compound (2):

with furan;

wherein the reaction is carried out in the absence of an acid; and

wherein the reaction is carried out in the absence of increased pressure(e.g., at approximately 1 atm).

The Diels-Alder reaction described above is carried out in the absenceof an acid. In certain embodiments, the reaction is carried out in theabsence of added acid (i.e., no acid is added to the reaction mixture).In certain embodiments, the reaction is carried out in the absence of aLewis acid. In certain embodiments, the reaction is carried out in theabsence of an added Lewis acid or Brønsted acid. In certain embodiments,the reaction mixture consists essentially of Compound (2), furan, andsolvent.

In certain embodiments, the reaction is carried out in the absence of aperchlorate. In certain embodiments, the reaction is carried out in theabsence of magnesium perchlorate (MgClO₄). In certain embodiments, thereaction is carried out in the absence of lithium perchlorate (LiClO₄).In certain embodiments, the reaction is carried out in the absence oflithium trifluoromethanesulfonimide. In certain embodiments, thereaction is carried out in the absence of one or more Lewis acidsdescribed in International Publication No. WO 2016/100732, publishedJun. 23, 2016, the entire contents of which is incorporated herein byreference.

The Diels-Alder reaction provided above is carried out in the absence ofincreased pressure (i.e., at approximately atmospheric pressure (1atm)).

In certain embodiments, the reaction is carried out in a solvent. Incertain embodiments, the solvent is a polar solvent. In certainembodiments, the Diels-Alder reaction is carried out in an aprotic polarsolvent (e.g., acetone, ethyl acetate, tetrahydrofuran, acetonitrile,N-Methyl-2-pyrrolidone (NMP), dimethyl formamide, dimethyl acetamide,1,3-dimethyl-2-imidazolidinone, sufolane, dimethylsulfone). In certainembodiments, the solvent is an amide, lactam, or urea such asN,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP),1,3-dimethyl-2-imidazolidinone (DMI), or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). In otherembodiments, the solvent is a sulfone (e.g., sufolane, dimethylsulfone).In certain embodiments, the solvent is NMP. In certain embodiments, thesolvent is a co-solvent comprising NMP. Other examples of polar solventsinclude, but are not limited to, ketones and nitriles, such as acetoneand acetonitrile. In certain embodiments, a polar solvent is selectedfrom the group consisting of DMF, NMP, DMI, DMPU, acetone, andacetonitrile. In certain embodiments, a polar solvent is selected fromthe group consisting of NMP, DMPU, acetone, and acetonitrile.

In certain embodiments, the reaction is carried out in the absence ofsolvent. In certain embodiments, the reaction is carried out in an ionicliquid. In certain embodiments, the reaction is carried out in aball-mill reactor.

The reaction can be carried out at any concentration of the reactants insolvent or reaction mixture. In certain embodiments, the concentrationof Compound (2) in solvent or reaction mixture is approximately 0.01molar (mol/L, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M, 0.06 M, 0.07 M, 0.08M, 0.09 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9M, 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, 10 M. In certainembodiments, the reaction is carried out at a concentration of 1-20 M insolution with respect to Compound (2). In certain embodiments, theconcentration is 5-15 M. In certain embodiments, the concentration is10-15 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately 20° C., 30° C., 40° C., 50° C., 60° C.,70° C., 80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or150° C. In certain embodiments, the reaction temperature is above 100°C. In certain embodiments, the reaction is carried out at a temperaturebelow 100° C. In certain embodiments, the reaction is carried out at atemperature above room temperature (21° C. or 70° F.). In certainembodiments, the temperature is between room temperature and 100° C. Incertain embodiments, the reaction is carried out at a temperaturebetween 30 and 60° C. In certain embodiments, the reaction is carriedout at a temperature between 40 and 50° C. In certain embodiments, thereaction is carried out at approximately 40° C., 41° C., 42° C., 43° C.,44° C., 45° C., 46° C., 47° C., 48° C., 49° C., or 50° C. In certainembodiments, the reaction is carried out at around 45° C.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

The reaction mixture may contain any ratio of the reactants,specifically, Compound (2) and furan. In certain embodiments, furan ispresent in greater than 1 equivalent relative to the amount of Compound(2) in the reaction mixture (i.e., excess). In certain embodiments, theratio of Compound (2) to furan in the reaction mixture is from 1:1 to1:20. In certain embodiments, the ratio of Compound (2) to furan in thereaction mixture is from 1:1 to 1:10. In certain embodiments, the ratioof Compound (2) to furan in the reaction mixture is approximately 1:2,1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15,1:16, 1:17, 1:18, 1:19, or 1:20. In certain embodiments, the ratio ofCompound (2) to furan in the reaction mixture is from 1:4 to 1:5. Incertain embodiments, the ratio of Compound (2) to furan in the reactionmixture is about 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8,or 1:4.9.

As described herein, the reaction may be carried out in the absence ofadded acid (e.g., Lewis and/or Brønsted acids) at approximately 1 atm.In some instances, the reaction solvent and temperature may be varied asfollows. In certain embodiments, the reaction is carried out in a polarsolvent at room temperature or above. In certain embodiments, thereaction is carried out in a polar solvent between room temperature and100° C. In certain embodiments, the reaction is carried out in a polarsolvent at elevated temperature (i.e., above room temperature). Incertain embodiments, the reaction is carried out in a polar solvent at atemperature between room temperature and 100° C. In certain embodiments,the reaction is carried out in a polar solvent at a temperature between30° C. and 100° C. In certain embodiments, the reaction is carried outin a polar solvent at a temperature between 30° C. and 60° C. In certainembodiments, the reaction is carried out in a polar solvent at atemperature between 40° C. and 50° C. In certain embodiments, thereaction is carried out in a polar solvent at a temperature around 50°C. In certain embodiments, the reaction is carried out in a polarsolvent at a temperature around 45° C. In certain embodiments, thereaction is carried out in a polar solvent at a temperature around 40°C. In certain embodiments, the reaction is carried out in NMP at roomtemperature or above. In certain embodiments, the reaction is carriedout in NMP at between room temperature and 100° C. In certainembodiments, the reaction is carried out in NMP at elevated temperature(i.e., above room temperature). In certain embodiments, the reaction iscarried out in NMP at a temperature between room temperature and 100° C.In certain embodiments, the reaction is carried out in NMP at atemperature between 30° C. and 100° C. In certain embodiments, thereaction is carried out in NMP at a temperature between 30° C. and 60°C. In certain embodiments, the reaction is carried out in NMP at atemperature between 40° C. and 50° C. In certain embodiments, thereaction is carried out in NMP at a temperature around 50° C. In certainembodiments, the reaction is carried out in NMP at a temperature around45° C. In certain embodiments, the reaction is carried out in NMP at atemperature around 40° C.

In the methods provided herein, Compound (1) can be formed as the exo orendo cycloadduct, or as a mixture of exo and endo cycloadducts. The“exo” and “endo” adducts are shown below:

For cantharidin, a high exo-to-endo ratio is desired. In certainembodiments, the Diels-Alder methods provided herein yield a favorableexo-to-endo ratio. For instance, the exo-to-endo product ratios producedby methods disclosed herein can be at least about 80:20, 81:19, 82:18,83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, 90:10, 91:9, 92:8,93:7, 94:6, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. The percentage ofexo product per total amount of product can be at least about 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, 99.999%, or 100%. In certainembodiments, the exo/endo ratio is from about 70:30 to 99:1. In certainembodiments, the exo/endo ratio is from about 70:30 to 90:10. In certainembodiments, the exo/endo ratio is from about 70:30 to 80:20. In certainembodiments, the exo/endo ratio is about 70:30, 71:29, 72:28, 73:27,74:26, 75:25, 76:24, 77:23, 78:22, 79:21, or 80:20. In certainembodiments, the exo/endo ratio is about 75:25. In certain embodiments,the exo/endo ratio is from about 80:20 to about 90:10. In certainembodiments, the exo/endo ratio is about 80:20. In certain embodiments,the exo/endo ratio is about 81:19. In certain embodiments, the exo/endoratio is about 82:18. In certain embodiments, the exo/endo ratio isabout 83:17. In certain embodiments, the exo/endo ratio is about 84:16.In certain embodiments, the exo/endo ratio is about 85:15. In certainembodiments, the exo/endo ratio is about 86:14. In certain embodiments,the exo/endo ratio is about 87:13. In certain embodiments, the exo/endoratio is about 88:12. In certain embodiments, the exo/endo ratio isabout 89:11. In certain embodiments, the exo/endo ratio is about 90:10.In certain embodiments, the exo/endo ratio is about 95:5. In certainembodiments, the exo/endo ratio is about 98:2. In certain embodiments,the exo/endo ratio is about 99:1. In certain embodiments, the exo/endoratio is about 99.10:0.10.

Any of these exo/endo ratios can be achieved by, in certain embodiments,reacting Compound (2) with furan in the absence of added acid, atapproximately atmospheric pressure, in an aprotic polar solvent (e.g.,NMP), with heating above room temperature (e.g., between roomtemperature and 100° C., e.g., between 40 and 50° C.). In certainembodiments, an exo/endo ratio of about 70:30 to about 90:10 is achievedby reacting Compound (2) with furan in the absence of added acid, atapproximately atmospheric pressure, in an aprotic polar solvent (e.g.,NMP), with heating above room temperature (e.g., between roomtemperature and 100° C., e.g., between 40 and 50° C.). In certainembodiments, an exo/endo ratio of about 80:20 to about 90:10 is achievedby reacting Compound (2) with furan in the absence of added acid, atapproximately atmospheric pressure, in an aprotic polar solvent (e.g.,NMP), with heating above room temperature (e.g., between roomtemperature and 100° C., e.g., between 40 and 50° C.). In certainembodiments, an exo/endo ratio of approximately 75:25 is achieved byreacting Compound (2) with furan in the absence of added acid, atapproximately atmospheric pressure, in an aprotic polar solvent (e.g.,NMP), with heating above room temperature (e.g., between roomtemperature and 100° C., e.g., between 40 and 50° C.). In certainembodiments, an exo/endo ratio of approximately 84:16 is achieved byreacting Compound (2) with furan in the absence of added acid, atapproximately atmospheric pressure, in an aprotic polar solvent (e.g.,NMP), with heating above room temperature (e.g., between roomtemperature and 100° C., e.g., between 40 and 50° C.).

Compound (1) can be formed in any chemical yield. In certainembodiments, the compound is produced in from 1-10%, 10-20% 20-30%,30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield. Incertain embodiments, the compound is produced in approximately 1%, 5%,10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 98%, 99%, or 100% yield. In certain embodiments,Compound (1) is isolated in greater than 50% yield. In certainembodiments, Compound (1) is isolated in about 50-60% yield. Thecompound may be isolated as a mixture or endo and exo products asdescribed above and herein.

In certain embodiments, Compound (1) can be prepared and isolated inhigh chemical purity by a method described herein. In certainembodiments, the Compound (1) is isolated in greater than 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In certainembodiments, Compound (1) is isolated in greater than 90% purity. Incertain embodiments, Compound (1) is isolated in greater than 95%purity. In certain embodiments, Compound (1) is isolated in greater than98% purity. In certain embodiments, Compound (1) is isolated in greaterthan 99% purity.

Any chemical yield can be achieved by, in certain embodiments, reactingCompound (2) with furan in the absence of added acid, at approximatelyatmospheric pressure, in an aprotic polar solvent (e.g., NMP), withheating above room temperature (e.g., between room temperature and 100°C., e.g., between 40 and 50° C.). For example, in certain embodiments, achemical yield for Compound (1) of at least 50% can be achieved byreacting Compound (2) with furan in the absence of added acid, atapproximately atmospheric pressure, in an aprotic polar solvent (e.g.,NMP), with heating above room temperature (e.g., between roomtemperature and 100° C., e.g., between 40 and 50° C.). In certainembodiments, a chemical yield for Compound (1) of 50-60% can be achievedby reacting Compound (2) with furan in the absence of added acid, atapproximately atmospheric pressure, in an aprotic polar solvent (e.g.,NMP), with heating above room temperature (e.g., between roomtemperature and 100° C., e.g., between 40 and 50° C.).

After formation, Compound (1) may be purified via one or morepurification steps. For example, in certain embodiments, Compound (1) ispurified by chromatography, extraction, filtration, precipitation,crystallization, trituration, or any other method known in the art. Incertain embodiments, the compound is carried forward to a subsequentsynthetic step without purification (i.e., crude). In certainembodiments, the purification step improves the exo/endo ratio of theproduct mixture.

In certain embodiments, the reaction to prepare Compound (1) describedherein is followed by a step of recrystallizing Compound (1). Compound(1) may be recrystallized from any solvent or mixture of solvents. Incertain embodiments, Compound (1) is dissolved in a solvent, and then asecond solvent is added to the solution to facilitate the precipitationof recrystallized Compound (1). For instance, in certain embodiments,Compound (1) is recrystallized from ethyl acetate (EtOAc) and hexanes.For example, Compound (1) may be dissolved in EtOAc, and crystallineCompound (1) precipitates upon addition of hexanes to the solution. Thestep of recrystallizing may involve heating and/or cooling the solution.

In certain embodiments, the step of recrystallization improves theexo/endo ratio of the compound mixture. In certain embodiments, Compound(1) is isolated in an exo/endo ratio of greater than 90:10 afterrecrystallization. For example, in certain embodiments, Compound (1) isisolated in an exo/endo ratio of 95:5, 96:4, 97:3, 98:2, or 99:1 afterrecrystallization. In certain embodiments, Compound (1) is isolated ingreater than 30% yield after recrystallization. For example, in certainembodiments, Compound (1) is isolated in 30-40% yield afterrecrystallization.

As described herein, Compound (1) can be formed via a Diels-Alderreaction of Compound (2) with furan without the aid of acid or increasedpressure. This invention is significant for several reasons. Based onthe work of Dauben in the 1980s (See, e.g., JACS, 102, 6893(1980) andJOC, 50, 2576-2578 (1985)), this Diels-Alder cycloaddition was expectedto require exotic, highly demanding reaction conditions, such as extremepressures. At the time, precedent demonstrated that a retro Diels-Alderreaction of dehydrocantharidin and related systems was facile.Recognizing this, Dauben used exceedingly high pressures (>7 kbar) toforce the cycloaddition of Compound (2) to Compound (1). Later on,Grieco (see, e.g., JACS, 112, 4595-459 (1990)) used highly concentratedethereal solutions of lithium perchlorate (a Lewis acid) to promote thereaction. A second Grieco method using lithiumtrifluoromethanesulfonimide (a Lewis acid) also yielded the desiredadduct (1), but with erosion of the favorable exo-endo ratio. As notedherein, neither the Dauben nor the Grieco conditions are viablelarge-scale production methods for a commercial product. It was laterdiscovered that alternative Lewis acids could replace the lithium Lewisacids in the Grieco procedure (International Publication No. WO2016/100732, published Jun. 23, 2016, the entire contents of which isincorporated herein by reference).

The discovery that Compound (1) can be formed using the reactionconditions described herein is a surprising advancement. In particular,it is unexpected that Compound (1) can be formed from Compound (2) inthe absence of an acid promoter or with the aid of pressure. Forexample, in certain embodiments, mixing a solution of the two reactionsin an aprotic polar solvent (e.g., acetonitrile, NMP, DMPU, and acetone)with modest warming yields Compound (1) with a favorable ratio ofexo-endo isomers (e.g., greater than 80:20). Furthermore, in certainembodiments, isolation of the desired product Compound (1) could readilybe accomplished in favorable yield and in high purity. The fact thatsuch simple reaction conditions are all that is required for successfulformation of adduct (1) from Compound (2) and furan is surprising andunexpected based on 37 years of precedent. The success of these specificDiels-Alder conditions was not predicted for these two substrates.Notably, these new reactions conditions are quite suitable forindustrial-scale production of cantharidin. A reaction mixtureconsisting essentially of Compound (2), furan, and solvent is ideal forcommercial production as industrial hazards and toxic waste disposal areminimized.

As described herein, Compound (1) can be used to prepare cantharidin,for example, as shown in Scheme 6. Compound (1) can be hydrogenated andreduced to form cantharidin. In certain embodiments, the steps ofhydrogenation and reduction are carried out in the same reaction. Inother embodiments, the steps of hydrogenation and reduction are carriedout in separate, subsequent reactions.

Therefore, in certain embodiments, a method provided herein furthercomprises a step of hydrogenating Compound (1):

to give Compound (3):

The hydrogenation reaction may be carried out in the presence ofpalladium or platinum. The hydrogenation reaction may be performedusing, for example, Pd/C, Pd, PdCl₂, PtO₂, or Pt/C. In certainembodiments, the reaction may be performed in the presence of H₂. Thereaction may be carried out under transfer hydrogenation conditions(e.g., in the presence of 1,4-cyclohexadiene). The hydrogenationreaction may be carried out as described in International PublicationNo. WO 2016/100732, published Jun. 23, 2016, the entire contents ofwhich is incorporated herein by reference.

The hydrogenation reaction may be performed in a solvent. Examples ofsolvents are provided herein. In certain embodiments, the solvent isethyl acetate. The reaction can be carried out at any concentration ofthe reactants in solvent or reaction mixture. In certain embodiments,the concentration of Compound (1) in solvent or reaction mixture isapproximately 0.01 molar (mol/L, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M,0.06 M, 0.07 M, 0.08 M, 0.09 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, or10 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is greater than 150° C.In certain embodiments, the reaction temperature is approximately roomtemperature (21° C. or 70° F.). In certain embodiments, the reaction iscarried out at a temperature above room temperature. In certainembodiments, the temperature is between room temperature and 100° C.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

Compound (3) can be formed in any chemical yield. In certainembodiments, the compound is produced in from 1-10%, 10-20% 20-30%,30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield. Incertain embodiments, the compound is produced in approximately 1%, 5%,10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 98%, 99%, or 100% yield.

In certain embodiments, Compound (3) can be prepared and isolated inhigh chemical purity by a method described herein. In certainembodiments, Compound (3) is isolated in greater than 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In certainembodiments, Compound (3) is isolated in greater than 90% purity. Incertain embodiments, Compound (3) is isolated in greater than 95%purity. In certain embodiments, Compound (3) is isolated in greater than98% purity. In certain embodiments, Compound (3) is isolated in greaterthan 99% purity.

After formation, Compound (3) may be purified via one or morepurification steps. For example, in certain embodiments, Compound (3) ispurified by chromatography, extraction, filtration, precipitation,crystallization, or any other method known in the art. In certainembodiments, the compound is carried forward to a subsequent syntheticstep without purification (i.e., crude).

In certain embodiments, as shown in Scheme 6, the method furthercomprises a step of reducing Compound (3):

to yield cantharidin:

In certain embodiment, the reduction (also referred to as“desulfurization”) is carried out in the presence of a reducing agent.In certain embodiments, the reducing agent is Raney Nickel,Ni(II)/NaBH₄, Co(II)/NaBH₄, Li/EtNH₂, LAH/TiCl₃, LAH/CuCl₂, Ni(II)/Zn,Ni(II)/Al, or LAH/Cp₂Ni. In certain embodiments, the reducing agent isRaney Ni.

The reduction may be performed in a solvent. Examples of solvents areprovided herein. The reaction can be carried out at any concentration ofthe reactants in solvent or reaction mixture. In certain embodiments,the concentration of Compound (3) in solvent or reaction mixture isapproximately 0.01 molar (mol/L, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M,0.06 M, 0.07 M, 0.08 M, 0.09 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, or10 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is greater than 150° C.In certain embodiments, the reaction temperature is approximately roomtemperature (21° C. or 70° F.). In certain embodiments, the reaction iscarried out at a temperature above room temperature. In certainembodiments, the temperature is between room temperature and 100° C.Reaction temperatures can be from −20° C. to 100° C., in otherembodiments. In some instances, these reactions can be facilitated withthe aid of sonication or microwave heating.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

Cantharidin can be formed in any chemical yield. In certain embodiments,the compound is produced in from 1-10%, 10-20% 20-30%, 30-40%, 40-50%,50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield. In certainembodiments, the compound is produced in approximately 1%, 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% yield.

After formation, cantharidin may be purified via one or morepurification steps. For example, in certain embodiments, cantharidin ispurified by chromatography, extraction, filtration, precipitation,crystallization, or any other method known in the art. In certainembodiments, the compound is carried forward to a subsequent syntheticstep without purification (i.e., crude).

In certain embodiments, the steps of hydrogenating and reducing arecarried out in separate reactions. In certain embodiments, the steps ofhydrogenating and reducing are carried out in the same reaction. Thesteps of hydrogenating and reducing can be carried out in any order.Other examples of reagents and conditions useful in these hydrogenationand desulfurization reactions can be found in, e.g., InternationalPublication No. WO 2016/100732, published Jun. 23, 2016, the entirecontents of which is incorporated herein by reference.

In certain embodiments, cantharidin can be prepared and isolated in highchemical purity by a method described herein. In certain embodiments,cantharidin is isolated in greater than 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 98%, or 99% purity. In certain embodiments,cantharidin is isolated in greater than 90% purity. In certainembodiments, cantharidin is isolated in greater than 95% purity. Incertain embodiments, cantharidin is isolated in greater than 98% purity.In certain embodiments, cantharidin is isolated in greater than 99%purity. In certain embodiments, cantharidin is isolated in greater than99.1%. 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% purity.

Also provided herein are high-purity cantharidin compositions producedby any method described herein. A high-purity cantharidin composition,as described herein, is high-purity with respect to the cantharidincomponent of the composition (i.e., not taking into account other activeagents, excipients, carriers, solvents, etc. present in thecomposition). For instance, a high-purity cantharidin component of acomposition comprises a high concentration of cantharidin with respectto synthetic intermediates, reaction byproducts, or degradation productsof cantharidin. In certain embodiments, the purity is greater than 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% with respect tothe cantharidin component. In certain embodiments, the purity is greaterthan 90% with respect to the cantharidin component. In certainembodiments, the purity is greater than 95% with respect to thecantharidin component. In certain embodiments, the purity is greaterthan 98% with respect to the cantharidin component. In certainembodiments, the purity is greater than 99% with respect to thecantharidin component. In certain embodiments, the purity is greaterthan 99.1%. 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%purity.

Other Methods Useful in the Synthesis of Cantharidin

Scheme 5 outlines other methods provided herein which are useful in thepreparation of cantharidin and analogs thereof. Specifically,intermediates of Formula (IV) can be formed via novel Diels-Alderreaction between compounds of Formula (III) and furan. The Diels-Alderreaction can proceed with or without the aid of acid (e.g., Lewis acid),and with or without the aid of increased pressure. In certainembodiments, the Diels-Alder reaction proceeds without the aid of addedacid, and without the aid of increased pressure (i.e., at aroundatmospheric pressure). Compounds of Formula (IV) can then behydrogenated to provide compounds of Formula (V). Compounds of Formula(V) can then be transformed to cantharidin via two alternative routes,as shown in Scheme 5.

Provided herein are methods of preparing a compound of Formula (IV):

the methods comprising reacting a compound of Formula (III):

in the presence of furan, wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted acyl, ora nitrogen protecting group; or optionally two R^(N) on the samenitrogen are joined together with the intervening atoms to formoptionally substituted heterocyclyl or optionally substitutedheteroaryl; and

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

In certain embodiments, the reaction is carried out in the presence of aLewis acid. At least one Lewis acid may contain a Lewis metal selectedfrom the group consisting of Li(I), Mg(II), B(III), Al(III), Ti(IV),Zr(IV), Zn(II), Cu(I), Cu(II), Sn(II), Sn(IV), Si(IV), La(III), Sc(III),Yb(III), Eu(III), Ga(III), Sb(V), Nb(V), Fe(III), and Co(III). At leastone Lewis acid may be selected from lithium perchlorate, magnesiumperchlorate, aluminum chloride, lithium trifluoromethanesulfonate,lithium trifluoromethanesulfonamide, tin(II) trifluoromethanesulfonate,bis(cyclopentadienyl)zirconium(IV)bis(trifluoromethanesulfonate)tetrahydrofuran complex,bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), borontrifluoride diethyl etherate, and gallium(III) chloride. At least oneLewis acid may be selected from copper(II) tetrafluoroborate hydrate,aluminum bromide, niobium(V) chloride, ytterbium(III)trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate,magnesium trifluoromethanesulfonate, trimethylsilyltrifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate. Theconcentration of Lewis acid may be greater than or equal to 0.01 molar(moles/liter, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M, 0.06 M, 0.07 M, 0.08M, 0.09 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9M, 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, or 10 M.

The reaction can be carried out at any pressure. In certain embodiments,the reaction is carried out at a pressure of less than or equal to about1000 atmospheres (atm), 980 atm, 975 atm, 950 atm, 925 atm, 900 atm, 875atm, 850 atm, 825 atm, 800 atm, 775 atm, 750 atm, 725 atm, 700 atm, 675atm, 650 atm, 625 atm, 600 atm, 575 atm, 550 atm, 525 atm, 500 atm, 475atm, 450 atm, 425 atm, 400 atm, 375 atm, 350 atm, 325 atm, 300 atm, 275atm, 250 atm, 225 atm, 200 atm, 175 atm, 150 atm, 125 atm, 100 atm, 75atm, 50 atm, 45 atm, 40 atm, 35 atm, 30 atm, 25 atm, 20 atm, 15 atm, 10atm, 9 atm, 8 atm, 7 atm, 6 atm, 5 atm, 4 atm, 3 atm, 2 atm, or 1 atm.In certain embodiments, the reaction is carried out at a pressure above1000 atmospheres (atm).

The Diels-Alder reaction described may be carried out in the absence ofan acid. In certain embodiments, the reaction is carried out in theabsence of added acid (i.e., no acid is added to the reaction mixture).In certain embodiments, the reaction is carried out in the absence of anadded Lewis acid or Brønsted acid. In certain embodiments, the reactionmixture consists essentially of the compound of Formula (III), furan,and solvent.

In certain embodiments, the reaction is carried out in the absence of aperchlorate. In certain embodiments, the reaction is carried out in theabsence of magnesium perchlorate (MgClO₄). In certain embodiments, thereaction is carried out in the absence of lithium perchlorate (LiClO₄).In certain embodiments, the reaction is carried out in the absence ofbis(trifloromethanesulfonyl)imide. In certain embodiments, the reactionis carried out in the absence of one or more Lewis acids described inInternational Publication No. WO 2016/100732, published Jun. 23, 2016,the entire contents of which is incorporated herein by reference.

The Diels-Alder reaction provided above may be carried out in theabsence of increased pressure (i.e., at approximately atmosphericpressure (1 atm)).

In certain embodiments, the reaction is carried out in a solvent. Incertain embodiments, the solvent is a nonpolar or polar solvent. Incertain embodiments, the solvent is a polar solvent. For instance, incertain embodiments, reaction may be performed in acetone, toluene,benzene, xylenes, chlorobenzene, methylene chloride, ethylenedichloride, dioxane, tetrahydrofuran (THF), tert-butyl methyl ether,diisopropyl ether, 1,2-dimethoxyethane (glyme), acetonitrile, ethylacetate, isopropyl acetate, water, or a mixture thereof as the solvent.

In certain embodiments, the solvent is an amide, lactam, or urea such asN,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP),1,3-dimethyl-2-imidazolidinone (DMI), or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). In certainembodiments, the solvent is a sulfone solvent such as dimethyl sulfone,dimethyl sulfoxide (DMSO), or sulfolane. In certain embodiments, thesolvent is NMP. In certain embodiments, the solvent is a co-solventcomprising NMP. Other examples of polar solvents include, but are notlimited to, ketones and nitriles, such as acetone and acetonitrile. Incertain embodiments, an aprotic polar solvent is selected from the groupconsisting of DMF, NMP, DMI, DMPU, acetone, and acetonitrile. In certainembodiments, an aprotic polar solvent is selected from the groupconsisting of NMP, DMPU, acetone, and acetonitrile.

In certain embodiments, the reaction is carried out in the absence ofsolvent. In certain embodiments, the reaction is carried out in an ionicliquid. In certain embodiments, the reaction is carried out in aball-mill reactor.

The reaction can be carried out at any concentration of the reactants insolvent or reaction mixture. In certain embodiments, the concentrationof the compound of Formula (III). in solvent or reaction mixture isapproximately 0.01 molar (mol/L, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M,0.06 M, 0.07 M, 0.08 M, 0.09 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, or10 M. In certain embodiments, the reaction is carried out at aconcentration of 1-20 M in solution with respect to the compound ofFormula (III). In certain embodiments, the concentration is 5-15 M. Incertain embodiments, the concentration is 10-15 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is above 100° C. Incertain embodiments, the reaction is carried out at a temperature below100° C. In certain embodiments, the reaction is carried out at atemperature above room temperature (21° C. or 70° F.). In certainembodiments, the temperature is between room temperature and 100° C. Incertain embodiments, the reaction is carried out at a temperaturebetween 30 and 60° C. In certain embodiments, the reaction is carriedout at a temperature between 40 and 50° C. In certain embodiments, thereaction is carried out at approximately 40° C., 41° C., 42° C., 43° C.,44° C., 45° C., 46° C., 47° C., 48° C., 49° C., or 50° C. In certainembodiments, the reaction is carried out at around 45° C.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

The reaction mixture may contain any ratio of the reactants,specifically, the compound of Formula (III) and furan. In certainembodiments, furan is present in greater than 1 equivalent relative tothe amount of the compound of Formula (III) in the reaction mixture(i.e., excess). In certain embodiments, the ratio of the compound ofFormula (III) to furan in the reaction mixture is from 1:1 to 1:20. Incertain embodiments, the ratio of the compound of Formula (III) andfuran in the reaction mixture is from 1:1 to 1:10. In certainembodiments, the ratio of the compound of Formula (III) to furan in thereaction mixture is approximately 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8,1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or1:20. In certain embodiments, the ratio of the compound of Formula (III)to furan in the reaction mixture is from 1:4 to 1:5. In certainembodiments, the ratio of the compound of Formula (III) to furan in thereaction mixture is about 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6,1:4.7, 1:4.8, or 1:4.9.

As described herein, the reaction may be carried out in the absence ofadded acid at approximately 1 atm. In some instances, the reactionsolvent and temperature may be varied as follows. In certainembodiments, the reaction is carried out in a polar solvent at roomtemperature or above. In certain embodiments, the reaction is carriedout in a polar solvent between room temperature and 100° C. In certainembodiments, the reaction is carried out in a polar solvent at elevatedtemperature (i.e., above room temperature). In certain embodiments, thereaction is carried out in a polar solvent at a temperature between roomtemperature and 100° C. In certain embodiments, the reaction is carriedout in a polar solvent at a temperature between 30° C. and 100° C. Incertain embodiments, the reaction is carried out in a polar solvent at atemperature between 30° C. and 60° C. In certain embodiments, thereaction is carried out in a polar solvent at a temperature between 40°C. and 50° C. In certain embodiments, the reaction is carried out in apolar solvent at a temperature around 50° C. In certain embodiments, thereaction is carried out in an aprotic polar solvent at a temperaturearound 45° C. In certain embodiments, the reaction is carried out in apolar solvent at a temperature around 40° C. In certain embodiments, thereaction is carried out in NMP at room temperature or above. In certainembodiments, the reaction is carried out in NMP at between roomtemperature and 100° C. In certain embodiments, the reaction is carriedout in NMP at elevated temperature (i.e., above room temperature). Incertain embodiments, the reaction is carried out in NMP at a temperaturebetween room temperature and 100° C. In certain embodiments, thereaction is carried out in NMP at a temperature between 30° C. and 100°C. In certain embodiments, the reaction is carried out in NMP at atemperature between 30° C. and 60° C. In certain embodiments, thereaction is carried out in NMP at a temperature between 40° C. and 50°C. In certain embodiments, the reaction is carried out in NMP at atemperature around 50° C. In certain embodiments, the reaction iscarried out in NMP at a temperature around 45° C. In certainembodiments, the reaction is carried out in NMP at a temperature around40° C.

In the methods provided herein, the compound of Formula (IV) can beformed as the exo or endo cycloadduct, or as a mixture of exo and endocycloadducts. The “exo” and “endo” adducts are shown below:

For cantharidin, a high exo-to-endo ratio is desired. In certainembodiments, the Diels-Alder methods provided herein yield a favorableexo-to-endo ratio. For instance, the exo-to-endo product ratios producedby methods disclosed herein can be at least about 80:20, 81:19, 82:18,83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, 90:10, 91:9, 92:8,93:7, 94:6, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. The percentage ofexo product per total amount of product can be at least about 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, 99.999%, or 100%. In certainembodiments, the exo/endo ratio is from about 70:30 to 99:1. In certainembodiments, the exo/endo ratio is from about 70:30 to 90:10. In certainembodiments, the exo/endo ratio is from about 70:30 to 80:20. In certainembodiments, the exo/endo ratio is about 70:30, 71:29, 72:28, 73:27,74:26, 75:25, 76:24, 77:23, 78:22, 79:21, or 80:20. In certainembodiments, the exo/endo ratio is about 75:25. In certain embodiments,the exo/endo ratio is from about 80:20 to about 90:10. In certainembodiments, the exo/endo ratio is about 80:20. In certain embodiments,the exo/endo ratio is about 81:19. In certain embodiments, the exo/endoratio is about 82:18. In certain embodiments, the exo/endo ratio isabout 83:17. In certain embodiments, the exo/endo ratio is about 84:16.In certain embodiments, the exo/endo ratio is about 85:15. In certainembodiments, the exo/endo ratio is about 86:14. In certain embodiments,the exo/endo ratio is about 87:13. In certain embodiments, the exo/endoratio is about 88:12. In certain embodiments, the exo/endo ratio isabout 89:11. In certain embodiments, the exo/endo ratio is about 90:10.In certain embodiments, the exo/endo ratio is about 95:5. In certainembodiments, the exo/endo ratio is about 98:2. In certain embodiments,the exo/endo ratio is about 99:1. In certain embodiments, the exo/endoratio is about 99.10:0.10.

The compound of Formula (IV) can be formed in any chemical yield. Incertain embodiments, the compound is produced in from 1-10%, 10-20%20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%yield. In certain embodiments, the compound is produced in approximately1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% yield. In certainembodiments, the compound of Formula (IV) is isolated in greater than50% yield.

In certain embodiments, the compound of Formula (IV) can be prepared andisolated in high chemical purity by a method described herein. Incertain embodiments, the compound of Formula (IV) is isolated in greaterthan 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%purity. In certain embodiments, the compound of Formula (IV) is isolatedin greater than 90% purity. In certain embodiments, the compound ofFormula (IV) is isolated in greater than 95% purity. In certainembodiments, the compound of Formula (IV) is isolated in greater than98% purity. In certain embodiments, the compound of Formula (IV) isisolated in greater than 99% purity.

After formation, the compound of Formula (IV) may be purified via one ormore purification steps. For example, in certain embodiments, thecompound of Formula (IV) is purified by chromatography, extraction,filtration, precipitation, crystallization, trituration, or any othermethod known in the art. In certain embodiments, the compound is carriedforward to a subsequent synthetic step without purification (i.e.,crude). In certain embodiments, the purification step improves theexo/endo ratio of the product mixture.

In certain embodiments, the reaction to prepare the compound of Formula(IV) described herein is followed by a step of recrystallizing thecompound of Formula (IV). The compound of Formula (IV) may berecrystallized from any solvent or mixture of solvents. In certainembodiments, the compound of Formula (IV) is dissolved in a solvent, andthen a second solvent is added to the solution to facilitate theprecipitation of recrystallized the compound of Formula (IV).

In certain embodiments, the step of recrystallization improves theexo/endo ratio of the compound mixture. In certain embodiments, thecompound of Formula (IV) is isolated in an exo/endo ratio of greaterthan 90:10 after recrystallization. For example, in certain embodiments,the compound of Formula (IV) is isolated in an exo/endo ratio of 95:5,96:4, 97:3, 98:2, or 99:1 after recrystallization.

Also provided herein are methods of preparing a compound of Formula (V):

the methods comprising hydrogenating a compound of Formula (IV):

wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted acyl, ora nitrogen protecting group; or optionally two R^(N) on the samenitrogen are joined together with the intervening atoms to formoptionally substituted heterocyclyl or optionally substitutedheteroaryl;

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

The hydrogenation may be carried out in the presence of palladium orplatinum. The hydrogenation reaction may be performed using, forexample, Pd/C, Pd, PdCl₂, PtO₂, or Pt/C. In certain embodiments, thereaction may be performed in the presence of H₂. The reaction may becarried out under transfer hydrogenation conditions (e.g., in thepresence of 1,4-cyclohexadiene). Other reagents/conditions useful in thehydrogenation reaction are described in, e.g., International PublicationNo. WO 2016/100732, published Jun. 23, 2016, the entire contents ofwhich is incorporated herein by reference.

The hydrogenation reaction may be performed in a solvent. Examples ofsolvents are provided herein. In certain embodiments, the solvent isethyl acetate. The reaction can be carried out at any concentration ofthe reactants in solvent or reaction mixture. In certain embodiments,the concentration of the compound of Formula (IV) in solvent or reactionmixture is approximately 0.01 molar (mol/L, M), 0.02 M, 0.03 M, 0.04 M,0.05 M, 0.06 M, 0.07 M, 0.08 M, 0.09 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9M, or 10 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is greater than 150° C.In certain embodiments, the reaction temperature is approximately roomtemperature (21° C. or 70° F.). In certain embodiments, the reaction iscarried out at a temperature above room temperature. In certainembodiments, the temperature is between room temperature and 100° C.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

The compound of Formula (V) can be formed in any chemical yield. Incertain embodiments, the compound is produced in from 1-10%, 10-20%20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%yield. In certain embodiments, the compound is produced in approximately1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% yield.

In certain embodiments, the compound of Formula (V) can be prepared andisolated in high chemical purity by a method described herein. Incertain embodiments, the compound is isolated in greater than 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In certainembodiments, the compound of Formula (V) is isolated in greater than 90%purity. In certain embodiments, the compound of Formula (V) is isolatedin greater than 95% purity. In certain embodiments, the compound ofFormula (V) is isolated in greater than 98% purity. In certainembodiments, the compound of Formula (V) is isolated in greater than 99%purity.

After formation, the compound of Formula (V) may be purified via one ormore purification steps. For example, in certain embodiments, thecompound of Formula (V) is purified by chromatography, extraction,filtration, precipitation, crystallization, or any other method known inthe art. In certain embodiments, the compound is carried forward to asubsequent synthetic step without purification (i.e., crude).

Also provided herein is a method of preparing a compound of Formula(VI):

the method comprising reducing a compound of Formula (V):

wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group; oroptionally two R^(N) on the same nitrogen are joined together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl; and

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

In certain embodiment, the reduction (also referred to as“desulfurization”) is carried out in the presence of a reducing agent.In certain embodiments, the reducing agent is Raney Nickel,Ni(II)/NaBH₄, Co(II)/NaBH₄, Li/EtNH₂, LAH/TiCl₃, LAH/CuCl₂, Ni(II)/Zn,Ni(II)/Al, or LAH/Cp₂Ni. In certain embodiments, the reducing agent isRaney Ni. Other reagents/conditions useful in the reduction reaction aredescribed in, e.g., International Publication No. WO 2016/100732,published Jun. 23, 2016, the entire contents of which is incorporatedherein by reference.

The reduction may be performed in a solvent. Examples of solvents areprovided herein. The typical solvents for desulfurization reactions canbe alcohols, ethers, ester-based solvents and water or various mixturesof these solvents. The reaction can be carried out at any concentrationof the reactants in solvent or reaction mixture. In certain embodiments,the concentration of the compound of Formula (V) in solvent or reactionmixture is approximately 0.01 molar (mol/L, M), 0.02 M, 0.03 M, 0.04 M,0.05 M, 0.06 M, 0.07 M, 0.08 M, 0.09 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9M, or 10 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is greater than 150° C.In certain embodiments, the reaction temperature is approximately roomtemperature (21° C. or 70° F.). In certain embodiments, the reaction iscarried out at a temperature above room temperature. In certainembodiments, the temperature is between room temperature and 100° C.Reaction temperatures can be from −20° C. to 100° C., in otherembodiments. In some instances, these reactions can be facilitated withthe aid of sonication or microwave heating.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

The compound of Formula (VI) can be formed in any chemical yield. Incertain embodiments, the compound is produced in from 1-10%, 10-20%20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%yield. In certain embodiments, the compound is produced in approximately1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% yield.

In certain embodiments, the compound of Formula (VI) can be prepared andisolated in high chemical purity by a method described herein. Incertain embodiments, the compound of Formula (VI) is isolated in greaterthan 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%purity. In certain embodiments, the compound of Formula (VI) is isolatedin greater than 90% purity. In certain embodiments, the compound ofFormula (VI) is isolated in greater than 95% purity. In certainembodiments, the compound of Formula (VI) is isolated in greater than98% purity. In certain embodiments, the compound of Formula (VI) isisolated in greater than 99% purity.

After formation, the compound of Formula (VI) may be purified via one ormore purification steps. For example, in certain embodiments, thecompound of Formula (VI) is purified by chromatography, extraction,filtration, precipitation, crystallization, or any other method known inthe art. In certain embodiments, the compound is carried forward to asubsequent synthetic step without purification (i.e., crude).

Also provided herein is a method of preparing cantharidin:

the method comprising:

(a) hydrolyzing a compound of Formula (VI):

to yield a compound of the formula:

or a salt thereof; and

(b) dehydrating the compound formed in step (a) under suitableconditions to form cantharidin; wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group; oroptionally two R^(N) on the same nitrogen are joined together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl; and

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

In certain embodiments, the step of hydrolyzing (i.e., step (a)) iscarried out in the presence of a base. In certain embodiments, the baseis a hydroxide (e.g., NaOH, KOH, LiOH). In certain embodiments, thehydrolysis is carried out in the presence of water.

The reduction may be performed in a solvent. The reaction can be carriedout at any concentration of the reactants in solvent or reactionmixture. In certain embodiments, the concentration of the compound ofFormula (VI) in solvent or reaction mixture is approximately 0.01 molar(mol/L, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M, 0.06 M, 0.07 M, 0.08 M, 0.09M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, or 10 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is greater than 150° C.In certain embodiments, the reaction temperature is approximately roomtemperature (21° C. or 70° F.). In certain embodiments, the reaction iscarried out at a temperature above room temperature. In certainembodiments, the temperature is between room temperature and 100° C.Reaction temperatures can be from −20° C. to 100° C., in otherembodiments. In some instances, these reactions can be facilitated withthe aid of sonication or microwave heating.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

The compound of the formula:

can be formed in any chemical yield. In certain embodiments, thecompound is produced in from 1-10%, 10-20% 20-30%, 30-40%, 40-50%,50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield. In certainembodiments, the compound is produced in approximately 1%, 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% yield.

In certain embodiments, the compound can be prepared and isolated inhigh chemical purity by a method described herein. In certainembodiments, the compound is isolated in greater than 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In certainembodiments, the compound is isolated in greater than 90% purity. Incertain embodiments, the compound is isolated in greater than 95%purity. In certain embodiments, the compound is isolated in greater than98% purity. In certain embodiments, the compound is isolated in greaterthan 99% purity.

After formation, the compound of the formula:

may be purified via one or more purification steps. For example, incertain embodiments, the compound of is purified by chromatography,extraction, filtration, precipitation, crystallization, or any othermethod known in the art. In certain embodiments, the compound is carriedforward to a subsequent synthetic step without purification (i.e.,crude).

In certain embodiments, the step of dehydrating (i.e., step (b)) iscarried out in the presence of a reagent capable of effecting thedehydration. For example, in certain embodiments, acid chlorides, acidanhydrides, and mixed anhydrides (e.g., mixed anhydrides of sulfonic andphosphonic acids) can be used. In certain embodiments, propylphosphonicanhydride can be used. In certain embodiments, acetic anhydride, thionylchloride, or POCl₃ can be used.

The reduction may be performed in a solvent. The reaction can be carriedout at any concentration of the reactants in solvent or reactionmixture. In certain embodiments, the concentration of the startingmaterial in solvent or reaction mixture is approximately 0.01 molar(mol/L, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M, 0.06 M, 0.07 M, 0.08 M, 0.09M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, or 10 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is greater than 150° C.In certain embodiments, the reaction temperature is approximately roomtemperature (21° C. or 70° F.). In certain embodiments, the reaction iscarried out at a temperature above room temperature. In certainembodiments, the temperature is between room temperature and 100° C.Reaction temperatures can be from −20° C. to 100° C., in otherembodiments. In some instances, these reactions can be facilitated withthe aid of sonication or microwave heating.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

Cantharidin can be formed in any chemical yield. In certain embodiments,the compound is produced in from 1-10%, 10-20% 20-30%, 30-40%, 40-50%,50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield. In certainembodiments, the compound is produced in approximately 1%, 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% yield.

After formation, cantharidin may be purified via one or morepurification steps. For example, in certain embodiments, cantharidin ispurified by chromatography, extraction, filtration, precipitation,crystallization, or any other method known in the art. In certainembodiments, the compound is carried forward to a subsequent syntheticstep without purification (i.e., crude).

In certain embodiments, cantharidin can be prepared and isolated in highchemical purity by a method described herein. In certain embodiments,cantharidin is isolated in greater than 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 98%, or 99% purity. In certain embodiments,cantharidin is isolated in greater than 90% purity. In certainembodiments, cantharidin is isolated in greater than 95% purity. Incertain embodiments, cantharidin is isolated in greater than 98% purity.In certain embodiments, cantharidin is isolated in greater than 99%purity. In certain embodiments, cantharidin is isolated in greater than99.1%. 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% purity.Also provided herein is a high-purity cantharidin composition producedby any method described herein.

As shown in Scheme 5, also provided herein is a method of preparing aCompound (3):

the method comprising steps of:

(a) hydrolyzing a compound of Formula (V):

to yield a compound of the formula:

or a salt thereof; and

(b) dehydrating the compound formed in step (a) under suitableconditions to form Compound (3); wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group; oroptionally two R^(N) on the same nitrogen are joined together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl; and

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

In certain embodiments, the step of hydrolyzing (i.e., step (a)) iscarried out in the presence of a base. In certain embodiments, the baseis a hydroxide (e.g., NaOH, KOH, LiOH). In certain embodiments, thehydrolysis is carried out in the presence of water.

The reduction may be performed in a solvent. The reaction can be carriedout at any concentration of the reactants in solvent or reactionmixture. In certain embodiments, the concentration of the compound ofFormula (V) in solvent or reaction mixture is approximately 0.01 molar(mol/L, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M, 0.06 M, 0.07 M, 0.08 M, 0.09M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M or 10 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is greater than 150° C.In certain embodiments, the reaction temperature is approximately roomtemperature (21° C. or 70° F.). In certain embodiments, the reaction iscarried out at a temperature above room temperature. In certainembodiments, the temperature is between room temperature and 100° C.Reaction temperatures can be from −20° C. to 100° C., in otherembodiments. In some instances, these reactions can be facilitated withthe aid of sonication or microwave heating.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

The compound of the formula:

can be formed in any chemical yield. In certain embodiments, thecompound is produced in from 1-10%, 10-20% 20-30%, 30-40%, 40-50%,50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield. In certainembodiments, the compound is produced in approximately 1%, 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% yield.

In certain embodiments, the compound can be prepared and isolated inhigh chemical purity by a method described herein. In certainembodiments, the compound is isolated in greater than 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In certainembodiments, the compound is isolated in greater than 90% purity. Incertain embodiments, the compound is isolated in greater than 95%purity. In certain embodiments, the compound is isolated in greater than98% purity. In certain embodiments, the compound is isolated in greaterthan 99% purity.

After formation, the compound of the formula:

may be purified via one or more purification steps. For example, incertain embodiments, the compound of is purified by chromatography,extraction, filtration, precipitation, crystallization, or any othermethod known in the art. In certain embodiments, the compound is carriedforward to a subsequent synthetic step without purification (i.e.,crude).

In certain embodiments, the step of dehydrating (i.e., step (b)) iscarried out in the presence of a reagent capable of effecting thedehydration. For example, in certain embodiments, acid chlorides, acidanhydrides, and mixed anhydrides (e.g., mixed anhydrides of sulfonic andphosphonic acids) can be used. In certain embodiments, propylphosphonicanhydride can be used. In certain embodiments, acetic anhydride, thionylchloride, or POCl₃ can be used.

The reduction may be performed in a solvent. The reaction can be carriedout at any concentration of the reactants in solvent or reactionmixture. In certain embodiments, the concentration of the startingmaterial in solvent or reaction mixture is approximately 0.01 molar(mol/L, M), 0.02 M, 0.03 M, 0.04 M, 0.05 M, 0.06 M, 0.07 M, 0.08 M, 0.09M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 2M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, or 10 M.

The reaction may be carried out at any temperature. The reactiontemperature may be approximately −100° C., −90° C., −80° C., −78° C.,−70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10, 0° C., −10°C., 20° C., room temperature, 30° C., 40° C., 50° C., 60° C., 70° C.,80° C., 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., or 150° C.In certain embodiments, the reaction temperature is greater than 150° C.In certain embodiments, the reaction temperature is approximately roomtemperature (21° C. or 70° F.). In certain embodiments, the reaction iscarried out at a temperature above room temperature. In certainembodiments, the temperature is between room temperature and 100° C.Reaction temperatures can be from −20° C. to 100° C., in otherembodiments. In some instances, these reactions can be facilitated withthe aid of sonication or microwave heating.

The reaction may be carried out over any length of time. The reactiontime may be greater than or equal to 30 seconds, 1 minute, 5 minutes, 10minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, greaterthan 5 hours, 10 hours, greater than 10 hours, 15 hours, or 20 hours. Incertain embodiments, the reaction time is greater than 20 hours. Incertain embodiments, the reaction time is greater than or equal to 1day. In certain embodiments, the reaction time is greater than 1 day.

Compound (3) can be formed in any chemical yield. In certainembodiments, the compound is produced in from 1-10%, 10-20% 20-30%,30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield. Incertain embodiments, the compound is produced in approximately 1%, 5%,10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 98%, 99%, or 100% yield.

In certain embodiments, Compound (3) can be prepared and isolated inhigh chemical purity by a method described herein. In certainembodiments, Compound (3) is isolated in greater than 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In certainembodiments, Compound (3) is isolated in greater than 90% purity. Incertain embodiments, Compound (3) is isolated in greater than 95%purity. In certain embodiments, Compound (3) is isolated in greater than98% purity. In certain embodiments, Compound (3) is isolated in greaterthan 99% purity.

After formation, Compound (3) may be purified via one or morepurification steps. For example, in certain embodiments, cantharidin ispurified by chromatography, extraction, filtration, precipitation,crystallization, or any other method known in the art. In certainembodiments, the compound is carried forward to a subsequent syntheticstep without purification (i.e., crude).

In certain embodiments, the method further comprises a step of reducing(i.e., desulfurizing) Compound (3) to yield cantharidin. This step canbe carried out as described above and herein.

As defined herein, n is 0, 1, 2, 3, 4, or 5. In certain embodiments, nis 0. In certain embodiments, n is 1. In certain embodiments, n is 2. Incertain embodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5.

As defined herein, each instance of R³ is independently hydrogen,halogen, —CN, —NO₂, —N₃, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl, optionally substituted sulfonyl, optionallysubstituted sulfinyl, —OR^(O), —N(R^(N))₂, or —SR^(S). In certainembodiments, at least one instance of R³ is hydrogen. In certainembodiments, at least one instance of R³ is halogen. In certainembodiments, at least one instance of R³ is —CN. In certain embodiments,at least one instance of R³ is —NO₂. In certain embodiments, at leastone instance of R³ is —N₃. In certain embodiments, at least one instanceof R³ is optionally substituted alkyl. In certain embodiments, at leastone instance of R³ is optionally substituted alkenyl. In certainembodiments, at least one instance of R³ is optionally substitutedalkynyl. In certain embodiments, at least one instance of R³ isoptionally substituted carbocyclyl. In certain embodiments, at least oneinstance of R³ is optionally substituted heterocyclyl. In certainembodiments, at least one instance of R³ is optionally substituted aryl.In certain embodiments, at least one instance of R³ is optionallysubstituted heteroaryl. In certain embodiments, at least one instance ofR³ is optionally substituted acyl. In certain embodiments, at least oneinstance of R³ is optionally substituted sulfonyl. In certainembodiments, at least one instance of R³ is optionally substitutedsulfinyl. In certain embodiments, at least one instance of R³ is—OR^(O). In certain embodiments, at least one instance of R³ is—N(R^(N))₂. In certain embodiments, at least one instance of R³ is—SR^(S).

Methods of Preparing Other Cantharidin Intermediates

Also provided herein are methods of preparing a compound of Formula (I),which is useful as an intermediate in the synthesis of cantharidin andanalogs thereof. The methods of preparing a compound of Formula (I)involve a palladium-mediated carbonylation of a compound of Formula(II), as shown in Scheme 2 below.

Provided herein are methods of preparing a compound of Formula (I):

, the method comprising reacting a compound of Formula (II):

in the presence of palladium, carbon monoxide, and a reagent of theformula R²OH; wherein:

X¹ is halogen, optionally substituted sulfonate, or optionallysubstituted phosphate;

R¹ and R² are independently optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, or anoxygen protecting group.

The carbonylation reaction is carried out in the presence of palladium.In certain embodiments, the palladium is a palladium salt. In certainembodiments, the palladium is a palladium(II) salt. Examples ofpalladium(II) salts include, but are not limited to, palladium chloride(PdCl₂), palladium acetate (Pd(OAc)₂), and palladium trifluoroacetate(Pd(TFA)₂). In certain embodiments, Pd(OAc)₂ is used. In certainembodiments, Pd(PPh₃)₄ is used. In certain embodiments, Pd₂(dba)₃ isused. In certain embodiments, one or more ligands are used in additionto the palladium source. For instance, in certain embodiments,Pd₂(dba)₃/dppf is used in the reaction. In other embodiments,Pd(OAc)₂/PPh₃ is used in the reaction.

The palladium source may be present in the reaction in a catalyticamount relative to the compound of Formula (II). For example, in certainembodiments, the palladium is present in approximately 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98, or 99 mol % relative to thecompound of Formula (II). In certain embodiments, the palladium ispresent in 1-10 mol %. In certain embodiments, the palladium is presentin approximately 4 mol %. In certain embodiments, the palladium ispresent in approximately 5 mol %. In certain embodiments, the palladiumis present in approximately 6 mol %.

The carbonylation reaction may be carried out in the presence of one ormore palladium ligands. In certain embodiments, the reaction is carriedout in the presence of a phosphine ligand. In certain embodiments, thereaction is carried out in the presence of a triarylphosphine((aryl)₃P). In certain embodiments, the reaction is carried out in thepresence of triphenylphosphine (Ph₃P). In certain embodiments, thereaction is carried out in the presence of1,1′-bis(diphenylphosphino)ferrocene (dppf).

In certain embodiments, the phosphine is present in a catalytic amount.For example, in certain embodiments, the phosphine is present inapproximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,98, or 99 mol % relative to the compound of Formula (II). In certainembodiments, the phosphine is present in approximately 1-10 mol %. Incertain embodiments, the phosphine is present in approximately 1-20 mol%. In certain embodiments, the phosphine is present in approximately10-20 mol %. In certain embodiments, the phosphine is present inapproximately 3 mol %. In certain embodiments, the phosphine is presentin approximately 14 mol %.

The carbonylation reaction is carried out in the presence of an alcoholof formula R²OH. In certain embodiments, the alcohol is present inexcess (i.e., greater than 1 equivalent with respect to the compound ofFormula (II)). In certain embodiments, the alcohol of formula R²OH ispresent as a solvent or co-solvent. In certain embodiments, the alcoholis selected from the group consisting of methanol, ethanol, n-propanol,iso-propanol, n-butanol, iso-butanol, sec-butanol, and tert-butanol. Incertain embodiments, the alcohol is methanol. In certain embodiments,the alcohol is ethanol. In certain embodiments, the alcohol isn-propanol. In certain embodiments, the alcohol is iso-propanol. Incertain embodiments, the alcohol is n-butanol. In certain embodiments,the alcohol is iso-butanol. In certain embodiments, the alcohol issec-butanol. In certain embodiments, the alcohol is and tert-butanol.

The carbonylation reaction may be carried out in a solvent, or a mixtureof solvents (i.e., co-solvents). Solvents can be polar or non-polar,protic or aprotic. Any solvent may be used in the reactions describedherein, and the reactions are not limited to particular solvents orcombinations of solvents. Examples of solvents are provided herein. Incertain embodiments, the reaction is carried out in a polar solvent,such as DMF. In certain embodiments, the reaction is carried out in amixture of DMF and an alcohol (i.e., R²OH). In certain embodiments, thereaction is carried out in the presence of DMF and methanol.

The carbonylation reaction may be carried out at any temperature. Incertain embodiments, the reaction is carried out at or around roomtemperature (rt) (21° C. or 70° F.). In certain embodiments, thereaction is carried out at below room temperature (e.g., from −100° C.to 21° C.). In certain embodiments, a reaction is carried out at aboveroom temperature. In certain embodiment, a reaction is carried out at30, 40, 50, 60, 70, 80, 110, 120, 130, 140, or 150° C. In certainembodiments, a reaction is carried out at above 150° C.

In certain embodiments, the carbonylation is carried out in the presenceof palladium, CO, R²OH, and a phosphine. In certain embodiments, thecarbonylation is carried out in the presence of palladium, CO, R²OH, anda phosphine, in a polar solvent at around room temperature. In certainembodiments, the reaction is carried out in the presence of Pd(OAc)₂,CO, MeOH, and Ph₃P. In certain embodiments, the reaction is carried outin the presence of Pd(OAc)₂, CO, MeOH, and Ph₃P, in a polar solvent ataround room temperature. In certain embodiments, the reaction is carriedout in the presence of Pd(OAc)₂, CO, MeOH, and Ph₃P, in a DMF at aroundroom temperature. In certain embodiments, the reaction is carried out inthe presence of catalytic Pd(OAc)₂ (e.g., approximately 5 mol %), excessCO, excess MeOH, and catalytic Ph₃P (e.g., approximately 14 mol %). Incertain embodiments, the reaction is carried out in the presence ofcatalytic Pd(OAc)₂ (e.g., approximately 5 mol %), excess CO, excessMeOH, and catalytic Ph₃P (e.g., approximately 14 mol %), in DMF ataround room temperature.

In certain embodiments, the reaction is carried out in the presence ofPd₂(dba)₃, CO, MeOH, and dppf. In certain embodiments, the reaction iscarried out in the presence of Pd₂(dba)₃, CO, MeOH, and dppf, in a polarsolvent at around room temperature. In certain embodiments, the reactionis carried out in the presence of Pd₂(dba)₃, CO, MeOH, and dppf, in apolar solvent at above room temperature. In certain embodiments, thereaction is carried out in the presence of Pd₂(dba)₃, CO, MeOH, anddppf, in a DMF at around room temperature. In certain embodiments, thereaction is carried out in the presence of Pd₂(dba)₃, CO, MeOH, anddppf, in a DMF at above room temperature. In certain embodiments, thereaction is carried out in the presence of catalytic Pd₂(dba)₃ (e.g.,approximately 1.5 mol %), excess CO, excess MeOH, and catalytic dppf(e.g., approximately 3 mol %). In certain embodiments, the reaction iscarried out in the presence of catalytic Pd₂(dba)₃ (e.g., approximately1.5 mol %), excess CO, excess MeOH, and catalytic dppf (e.g.,approximately 3 mol %), in DMF at around room temperature. In certainembodiments, the reaction is carried out in the presence of catalyticPd₂(dba)₃ (e.g., approximately 1.5 mol %), excess CO, excess MeOH, andcatalytic dppf (e.g., approximately 3 mol %), in DMF at above roomtemperature.

The compound of Formula (II) may be isolated in any chemical yield. Incertain embodiments, the compound is produced in from 1-10%, 10-20%20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%yield. In certain embodiments, the chemical yield is greater than 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In certain embodiments,the chemical yield is greater than 50%. In certain embodiments, thechemical yield is greater than 60%. In certain embodiments, the chemicalyield is greater than 70%. In certain embodiments, the chemical yield isgreater than 80%. In certain embodiments, the chemical yield is greaterthan 90%. In certain embodiments, the chemical yield is greater than95%. In certain embodiments, the chemical yield is greater than 98%. Incertain embodiments, the chemical yield is greater than 99%.

In certain embodiments, the compound of Formula (II) can be prepared andisolated in high chemical purity by a method described herein. Incertain embodiments, the compound of Formula (II) is isolated in greaterthan 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%purity. In certain embodiments, the compound of Formula (II) is isolatedin greater than 90% purity. In certain embodiments, the compound ofFormula (II) is isolated in greater than 95% purity. In certainembodiments, the compound of Formula (II) is isolated in greater than98% purity. In certain embodiments, the compound of Formula (II) isisolated in greater than 99% purity.

Methods described herein may further comprise one or more purificationsteps. For example, in certain embodiments, a compound produced by amethod described herein may be purified by chromatography, extraction,filtration, precipitation, crystallization, or any other method known inthe art. In certain embodiments, a compound or mixture is carriedforward to the next synthetic step without purification (i.e., crude).

As defined herein, X¹ is halogen, optionally substituted sulfonate,optionally substituted phosphate. In certain embodiments, X¹ is halogen(e.g., —Br, —I, —Cl, —F). In certain embodiments, X¹ is optionallysubstituted phosphate. In certain embodiments, X¹ is optionallysubstituted sulfonate. In certain embodiments, X¹ is —OSO₂-alkyl. Incertain embodiments, X¹ is mesylate (—OSO₂CH₃; “OMs”). In certainembodiments, X¹ is —OSO₂-aryl. In certain embodiments, X¹ is —OSO₂Ph. Incertain embodiments, X¹ is tosylate (—OSO₂C₆H₄p-CH₃; “OTs”). In certainembodiments, X¹ is triflate (—OSO₂CF₃; “OTf”). In certain embodiments,X¹ is brosylate (—OSO₂C₆H₄p-Br; “OBs”), In certain embodiments, X¹ isnonaflate (—OSO₂(CF₂)₃CF₃; “ONf”). In certain embodiments, X¹ isnosylate (—SO₂C₆H₄p-NO₂ or —SO₂C₆H₄o-NO₂; “ONs”). In certainembodiments, X¹ is dansylate (“ODs”).

In certain embodiments, X¹ is a leaving group. “Leaving group” isdefined herein.

As defined herein, R¹ is optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, or anoxygen protecting group. In certain embodiments, R¹ is optionallysubstituted alkyl. In certain embodiments, R¹ is optionally substitutedaryl. In certain embodiments, R¹ is optionally substituted heteroaryl.In certain embodiments, R¹ is optionally substituted carbocyclyl. Incertain embodiments, R¹ is optionally substituted heterocyclyl. Incertain embodiments, R¹ is an oxygen protecting group. In certainembodiments, R¹ is optionally substituted C₁₋₆ alkyl. In certainembodiments, R¹ is unsubstituted C₁₋₆ alkyl. In certain embodiments, R¹is optionally substituted C₁₋₄ alkyl. In certain embodiments, R¹ isunsubstituted C₁₋₄ alkyl. In certain embodiments, R¹ is methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Incertain embodiments, R¹ is methyl.

As defined herein, R² is optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, or anoxygen protecting group. In certain embodiments, R² is optionallysubstituted alkyl. In certain embodiments, R² is optionally substitutedaryl. In certain embodiments, R² is optionally substituted heteroaryl.In certain embodiments, R² is optionally substituted carbocyclyl. Incertain embodiments, R² is optionally substituted heterocyclyl. Incertain embodiments, R² is an oxygen protecting group. In certainembodiments, R² is optionally substituted C₁₋₆ alkyl. In certainembodiments, R² is unsubstituted C₁₋₆ alkyl. In certain embodiments, R²is optionally substituted C₁₋₄ alkyl. In certain embodiments, R² isunsubstituted C₁₋₄ alkyl. In certain embodiments, R² is methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Incertain embodiments, R² is methyl.

In certain embodiments, R¹ and R² are the same. In certain embodiments,R¹ and R² are different. In certain embodiments, both R¹ and R² aremethyl.

In certain embodiments, the compound of Formula (I) is of the formula:

In certain embodiments, the compound of Formula (II) is of the formula:

In certain embodiments, the compound of Formula (II) is of the formula:

In certain embodiments, X¹ is a sulfonate, R¹ is optionally substitutedalkyl, and the carbonylation is carried out in the presence ofpalladium, CO, R²OH (R² is optionally substituted alkyl), and aphosphine. In certain embodiments, X¹ is a sulfonate, R¹ is optionallysubstituted alkyl, and the carbonylation is carried out in the presenceof palladium, CO, R²OH (R² is optionally substituted alkyl), and aphosphine, in a polar solvent at around room temperature. In certainembodiments, X¹ is a triflate, R¹ is optionally substituted alkyl, andthe carbonylation is carried out in the presence of palladium, CO, R²OH(R² is optionally substituted alkyl), and a phosphine. In certainembodiments, X¹ is a triflate, R¹ is optionally substituted alkyl, andthe carbonylation is carried out in the presence of palladium, CO, R²OH(R² is optionally substituted alkyl), and a phosphine, in an solvent ataround room temperature. In certain embodiments, X¹ is triflate, R¹ ismethyl, and the carbonylation is carried out in the presence ofpalladium, CO, MeOH, and a phosphine. In certain embodiments, X¹ istriflate, R¹ is methyl, and the carbonylation is carried out in thepresence of palladium, CO, MeOH, and a phosphine, in a polar solvent ataround room temperature. In certain embodiments, X¹ is triflate, R¹ ismethyl, and the reaction is carried out in the presence of Pd(OAc)₂, CO,MeOH, and Ph₃P. In certain embodiments, X¹ is triflate, R¹ is methyl,and the reaction is carried out in the presence of Pd(OAc)₂, CO, MeOH,and Ph₃P, in a polar solvent at around room temperature. In certainembodiments, X¹ is triflate, R¹ is methyl, and the reaction is carriedout in the presence of Pd(OAc)₂, CO, and Ph₃P, in DMF/MeOH at aroundroom temperature. In certain embodiments, X¹ is triflate, R¹ is methyl,and the reaction is carried out in the presence of catalytic Pd(OAc)₂(e.g., approximately 5 mol %), excess CO, excess MeOH, and catalyticPh₃P (e.g., approximately 14 mol %). In certain embodiments, X¹ istriflate, R¹ is methyl, and the reaction is carried out in the presenceof catalytic Pd(OAc)₂ (e.g., approximately 5 mol %), excess CO, andcatalytic Ph₃P (e.g., approximately 14 mol %), in DMF/MeOH at aroundroom temperature.

Compounds

Also provided herein are compounds (i.e., intermediates) useful in thesynthesis of cantharidin and analogs thereof. In certain embodiments, acompound provided herein is useful as a medicament (e.g., for thetreatment of an infectious disease). For example, compounds of Formulae(IV), (V), and (VI), and pharmaceutically acceptable salts thereof, areuseful for treating diseases or conditions in a subject in need thereof.

In one aspect, the present invention provides compounds of Formula (II):

wherein:

X¹ is halogen, optionally substituted sulfonate, or optionallysubstituted phosphate;

R¹ is optionally substituted alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, or an oxygen protecting group.

As defined herein, X¹ is halogen, optionally substituted sulfonate,optionally substituted phosphonate. In certain embodiments, X¹ ishalogen (e.g., —Br, —I, —Cl). In certain embodiments, X¹ is optionallysubstituted phosphate. In certain embodiments, X¹ is optionallysubstituted sulfonate. In certain embodiments, X¹ is —OSO₂-alkyl. Incertain embodiments, X¹ is mesylate (—OSO₂CH₃; “OMs”). In certainembodiments, X¹ is —OSO₂-aryl. In certain embodiments, X¹ is —OSO₂Ph. Incertain embodiments, X¹ is tosylate (—OSO₂C₆H₄p-CH₃; “OTs”). In certainembodiments, X¹ is triflate (—OSO₂CF₃; “OTf”). In certain embodiments,X¹ is brosylate (—OSO₂C₆H₄p-Br; “OBs”), In certain embodiments, R¹ isnonaflate (—OSO₂(CF₂)₃CF₃; “ONf”). In certain embodiments, X¹ isnosylate (—SO₂C₆H₄p-NO₂ or —SO₂C₆H₄o-NO₂; “ONs”). In certainembodiments, X¹ is dansylate (“ODs”).

In certain embodiments, X¹ is a leaving group. “Leaving group” isdefined herein.

As defined herein, R¹ is optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, or anoxygen protecting group. In certain embodiments, R¹ is optionallysubstituted alkyl. In certain embodiments, R¹ is optionally substitutedaryl. In certain embodiments, R¹ is optionally substituted heteroaryl.In certain embodiments, R¹ is optionally substituted carbocyclyl. Incertain embodiments, R¹ is optionally substituted heterocyclyl. Incertain embodiments, R¹ is an oxygen protecting group. In certainembodiments, R¹ is optionally substituted C₁₋₆ alkyl. In certainembodiments, R¹ is unsubstituted C₁₋₆ alkyl. In certain embodiments, R¹is optionally substituted C₁₋₄ alkyl. In certain embodiments, R¹ isunsubstituted C₁₋₄ alkyl. In certain embodiments, R¹ is methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Incertain embodiments, R¹ is methyl.

As defined herein, R² is optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, or anoxygen protecting group. In certain embodiments, R² is optionallysubstituted alkyl. In certain embodiments, R² is optionally substitutedaryl. In certain embodiments, R² is optionally substituted heteroaryl.In certain embodiments, R² is optionally substituted carbocyclyl. Incertain embodiments, R² is optionally substituted heterocyclyl. Incertain embodiments, R² is an oxygen protecting group. In certainembodiments, R² is optionally substituted C₁₋₆ alkyl. In certainembodiments, R² is unsubstituted C₁₋₆ alkyl. In certain embodiments, R²is optionally substituted C₁₋₄ alkyl. In certain embodiments, R² isunsubstituted C₁₋₄ alkyl. In certain embodiments, R² is methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Incertain embodiments, R² is methyl.

In certain embodiments, R¹ and R² are the same. In certain embodiments,R¹ and R² are different. In certain embodiments, both R¹ and R² aremethyl.

In certain embodiments, the compound of Formula (II) is of the formula:

In certain embodiments, the compound of Formula (II) is of the formula:

Also provided herein are compounds of Formula (IV):

and pharmaceutically acceptable salts thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group; oroptionally two R^(N) on the same nitrogen are joined together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl;

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

Also provided herein are compounds of Formula (V):

and pharmaceutically acceptable salts thereof, wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group; oroptionally two R^(N) on the same nitrogen are joined together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl;

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

Also provided herein are compounds of Formula (III):

wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group; oroptionally two R^(N) on the same nitrogen are joined together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl;

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

Also provided herein are compounds of Formula (VI):

wherein:

n is 0, 1, 2, 3, 4, or 5;

each instance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S);

each instance of R^(O) is independently hydrogen, optionally substitutedalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted acyl, or an oxygen protecting group;

each instance of R^(N) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a nitrogen protecting group; oroptionally two R^(N) on the same nitrogen are joined together with theintervening atoms to form optionally substituted heterocyclyl oroptionally substituted heteroaryl; and

each instance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group.

As defined herein, n is 0, 1, 2, 3, 4, or 5. In certain embodiments, nis 0. In certain embodiments, n is 1. In certain embodiments, n is 2. Incertain embodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5.

As defined herein, each instance of R³ is independently hydrogen,halogen, —CN, —NO₂, —N₃, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl, optionally substituted sulfonyl, optionallysubstituted sulfinyl, —OR^(O), —N(R^(N))₂, or —SR^(S). In certainembodiments, at least one instance of R³ is hydrogen. In certainembodiments, at least one instance of R³ is halogen. In certainembodiments, at least one instance of R³ is —CN. In certain embodiments,at least one instance of R³ is —NO₂. In certain embodiments, at leastone instance of R³ is —N₃. In certain embodiments, at least one instanceof R³ is optionally substituted alkyl. In certain embodiments, at leastone instance of R³ is optionally substituted alkenyl. In certainembodiments, at least one instance of R³ is optionally substitutedalkynyl. In certain embodiments, at least one instance of R³ isoptionally substituted carbocyclyl. In certain embodiments, at least oneinstance of R³ is optionally substituted heterocyclyl. In certainembodiments, at least one instance of R³ is optionally substituted aryl.In certain embodiments, at least one instance of R³ is optionallysubstituted heteroaryl. In certain embodiments, at least one instance ofR³ is optionally substituted acyl. In certain embodiments, at least oneinstance of R³ is optionally substituted sulfonyl. In certainembodiments, at least one instance of R³ is optionally substitutedsulfinyl. In certain embodiments, at least one instance of R³ is—OR^(O). In certain embodiments, at least one instance of R³ is—N(R^(N))₂. In certain embodiments, at least one instance of R³ is—SR^(S).

Pharmaceutical Compositions, Kits, and Administration

The present disclosure provides pharmaceutical compositions comprising acompound of Formula (IV), (V), or (VI), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient. In certainembodiments, the compound described herein is provided in an effectiveamount in the pharmaceutical composition. In certain embodiments, theeffective amount is a therapeutically effective amount. In certainembodiments, the effective amount is a prophylactically effectiveamount. In certain embodiments, the effective amount is an amounteffective for treating an infectious disease or skin condition in asubject in need thereof.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include bringing the compound described herein (i.e., the“active ingredient” or “active compound”) into association with acarrier or excipient, and/or one or more other accessory ingredients,and then, if necessary and/or desirable, shaping, and/or packaging theproduct into a desired single- or multi-dose unit. In certainembodiments, the “active ingredient” or “active compound” is a compoundof Formula (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage, such as one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.In certain embodiments the composition may comprise between 0.1% and100% (w/w) active ingredient.

In some cases, a composition can comprise at least about 50% (w/v) ofactive compound, at least about 10% (w/v) of active compound, at leastabout 5% (w/v) of active compound, at least about 1% (w/v) of activecompound, at least about 0.75% (w/v) of active compound, at least about0.5% (w/v) of active compound, at least about 0.1% (w/v) of activecompound, at least about 0.01% (w/v) of active compound, or at leastabout 0.001% (w/v) of active compound. The active compound may bepresent in an amount between about 0.001% and 50% by weight, or betweenabout 1% and about 10% by weight, or between about 0.001% and 1% byweight.

A pharmaceutical composition can have an active compound concentration(milligram (mg) active ingredient/milliliter (mL) formulation) of about0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1.0 mg/mL, 1.1 mg/mL, 1.2 mg/mL, 1.3 mg/mL,1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, 2.0mg/mL, 2.1 mg/mL, 2.2 mg/mL, 2.3 mg/mL, 2.4 mg/mL, 2.5 mg/mL, 2.6 mg/mL,2.7 mg/mL, 2.8 mg/mL, 2.9 mg/mL, 3.0 mg/mL, 3.1 mg/mL, 3.2 mg/mL, 3.3mg/mL, 3.4 mg/mL, 3.5 mg/mL, 3.6 mg/mL, 3.7 mg/mL, 3.8 mg/mL, 3.9 mg/mL,4.0 mg/mL, 4.1 mg/mL, 4.2 mg/mL, 4.3 mg/mL, 4.4 mg/mL, 4.5 mg/mL, 4.6mg/mL, 4.7 mg/mL, 4.8 mg/mL, 4.9 mg/mL, 5.0 mg/mL, 5.1 mg/mL, 5.2 mg/mL,5.3 mg/mL, 5.4 mg/mL, 5.5 mg/mL, 5.6 mg/mL, 5.7 mg/mL, 5.8 mg/mL, 5.9mg/mL, 6.0 mg/mL, 6.1 mg/mL, 6.2 mg/mL, 6.3 mg/mL, 6.4 mg/mL, 6.5 mg/mL,6.6 mg/mL, 6.7 mg/mL, 6.8 mg/mL, 6.9 mg/mL, 7.0 mg/mL, 7.1 mg/mL, 7.2mg/mL, 7.3 mg/mL, 7.4 mg/mL, 7.5 mg/mL, 7.6 mg/mL, 7.7 mg/mL, 7.8 mg/mL,7.9 mg/mL, 8.0 mg/mL, 8.1 mg/mL, 8.2 mg/mL, 8.3 mg/mL, 8.4 mg/mL, 8.5mg/mL, 8.6 mg/mL, 8.7 mg/mL, 8.8 mg/mL, 8.9 mg/mL, 9.0 mg/mL, 9.1 mg/mL,9.2 mg/mL, 9.3 mg/mL, 9.4 mg/mL, 9.5 mg/mL, 9.6 mg/mL, 9.7 mg/mL, 9.8mg/mL, 9.9 mg/mL, 10.0 mg/mL, 10.1 mg/mL, 10.2 mg/mL, 10.3 mg/mL, 10.4mg/mL, 10.5 mg/mL, 10.6 mg/mL, 10.7 mg/mL, 10.8 mg/mL, 10.9 mg/mL, 11.0mg/mL, 11.1 mg/mL, 11.2 mg/mL, 11.3 mg/mL, 11.4 mg/mL, 11.5 mg/mL, 11.6mg/mL, 11.7 mg/mL, 11.8 mg/mL, 11.9 mg/mL, 12.0 mg/mL, 12.1 mg/mL, 12.2mg/mL, 12.3 mg/mL, 12.4 mg/mL, 12.5 mg/mL, 12.6 mg/mL, 12.7 mg/mL, 12.8mg/mL, 12.9 mg/mL, 13.0 mg/mL, 13.1 mg/mL, 13.2 mg/mL, 13.3 mg/mL, 13.4mg/mL, 13.5 mg/mL, 13.6 mg/mL, 13.7 mg/mL, 13.8 mg/mL, 13.9 mg/mL, 14.0mg/mL, 14.1 mg/mL, 14.2 mg/mL, 14.3 mg/mL, 14.4 mg/mL, 14.5 mg/mL, 14.6mg/mL, 14.7 mg/mL, 14.8 mg/mL, 14.9 mg/mL, 15.0 mg/mL, 15.5 mg/mL, 16.0mg/mL, 16.5 mg/mL, 17.0 mg/mL, 17.5 mg/mL, 18.0 mg/mL, 18.5 mg/mL, 19.0mg/mL, 19.5 mg/mL, or 20.0 mg/mL. In some examples, the activeingredient concentration is an amount of 0.5 milligrams (mg) to 20 mgper milliliter (ml), or 1 mg to 10 mg per ml.

As an alternative, a pharmaceutical composition can have an activeingredient concentration (mg active ingredient/mL formulation) of atleast about 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1.0 mg/mL, 1.1 mg/mL, 1.2 mg/mL,1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9mg/mL, 2.0 mg/mL, 2.1 mg/mL, 2.2 mg/mL, 2.3 mg/mL, 2.4 mg/mL, 2.5 mg/mL,2.6 mg/mL, 2.7 mg/mL, 2.8 mg/mL, 2.9 mg/mL, 3.0 mg/mL, 3.1 mg/mL, 3.2mg/mL, 3.3 mg/mL, 3.4 mg/mL, 3.5 mg/mL, 3.6 mg/mL, 3.7 mg/mL, 3.8 mg/mL,3.9 mg/mL, 4.0 mg/mL, 4.1 mg/mL, 4.2 mg/mL, 4.3 mg/mL, 4.4 mg/mL, 4.5mg/mL, 4.6 mg/mL, 4.7 mg/mL, 4.8 mg/mL, 4.9 mg/mL, 5.0 mg/mL, 5.1 mg/mL,5.2 mg/mL, 5.3 mg/mL, 5.4 mg/mL, 5.5 mg/mL, 5.6 mg/mL, 5.7 mg/mL, 5.8mg/mL, 5.9 mg/mL, 6.0 mg/mL, 6.1 mg/mL, 6.2 mg/mL, 6.3 mg/mL, 6.4 mg/mL,6.5 mg/mL, 6.6 mg/mL, 6.7 mg/mL, 6.8 mg/mL, 6.9 mg/mL, 7.0 mg/mL, 7.1mg/mL, 7.2 mg/mL, 7.3 mg/mL, 7.4 mg/mL, 7.5 mg/mL, 7.6 mg/mL, 7.7 mg/mL,7.8 mg/mL, 7.9 mg/mL, 8.0 mg/mL, 8.1 mg/mL, 8.2 mg/mL, 8.3 mg/mL, 8.4mg/mL, 8.5 mg/mL, 8.6 mg/mL, 8.7 mg/mL, 8.8 mg/mL, 8.9 mg/mL, 9.0 mg/mL,9.1 mg/mL, 9.2 mg/mL, 9.3 mg/mL, 9.4 mg/mL, 9.5 mg/mL, 9.6 mg/mL, 9.7mg/mL, 9.8 mg/mL, 9.9 mg/mL, 10.0 mg/mL, 10.1 mg/mL, 10.2 mg/mL, 10.3mg/mL, 10.4 mg/mL, 10.5 mg/mL, 10.6 mg/mL, 10.7 mg/mL, 10.8 mg/mL, 10.9mg/mL, 11.0 mg/mL, 11.1 mg/mL, 11.2 mg/mL, 11.3 mg/mL, 11.4 mg/mL, 11.5mg/mL, 11.6 mg/mL, 11.7 mg/mL, 11.8 mg/mL, 11.9 mg/mL, 12.0 mg/mL, 12.1mg/mL, 12.2 mg/mL, 12.3 mg/mL, 12.4 mg/mL, 12.5 mg/mL, 12.6 mg/mL, 12.7mg/mL, 12.8 mg/mL, 12.9 mg/mL, 13.0 mg/mL, 13.1 mg/mL, 13.2 mg/mL, 13.3mg/mL, 13.4 mg/mL, 13.5 mg/mL, 13.6 mg/mL, 13.7 mg/mL, 13.8 mg/mL, 13.9mg/mL, 14.0 mg/mL, 14.1 mg/mL, 14.2 mg/mL, 14.3 mg/mL, 14.4 mg/mL, 14.5mg/mL, 14.6 mg/mL, 14.7 mg/mL, 14.8 mg/mL, 14.9 mg/mL, 15.0 mg/mL, 15.5mg/mL, 16.0 mg/mL, 16.5 mg/mL, 17.0 mg/mL, 17.5 mg/mL, 18.0 mg/mL, 18.5mg/mL, 19.0 mg/mL, 19.5 mg/mL, or 20.0 mg/mL. In some situations, theformulation can have an active ingredient concentration that is lessthan or equal to about 40 mg/mL, 30 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL,or 1 mg/mL.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g., acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays(e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminumsilicate)), long chain amino acid derivatives, high molecular weightalcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.,carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60),polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate(Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate(Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80),polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45),polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g., Cremophor®),polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g., cornstarch and starchpaste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g., acacia, sodium alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate(Veegum®), and larch arabogalactan), alginates, polyethylene oxide,polyethylene glycol, inorganic calcium salts, silicic acid,polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, antiprotozoanpreservatives, alcohol preservatives, acidic preservatives, and otherpreservatives. In certain embodiments, the preservative is anantioxidant. In other embodiments, the preservative is a chelatingagent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®,Kathon®, and Euxyl®.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are topical in nature.

Dosage forms for topical and/or transdermal administration of a compounddescribed herein may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier or excipient and/or any neededpreservatives and/or buffers as can be required. Such dosage forms canbe prepared, for example, by dissolving and/or dispensing the activeingredient in the proper medium. Alternatively or additionally, the ratecan be controlled by either providing a rate controlling membrane and/orby dispersing the active ingredient in a polymer matrix and/or gel.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi-liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions. Topicallyadministrable formulations may, for example, comprise from about 1% toabout 10% (w/w) active ingredient, although the concentration of theactive ingredient can be as high as the solubility limit of the activeingredient in the solvent. Formulations for topical administration mayfurther comprise one or more of the additional ingredients describedherein.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. An effective amount may be included in a single dose ormultiple doses.

A composition may be delivered to a subject (e.g., to a skin area of thesubject having or suspected of having a wart or cutaneous lesion) fromonce a day to once a month or more. As an alternative or in addition to,a composition may be delivered to a subject from once a day to once aweek. As an alternative or in addition to, a composition may bedelivered to a subject at least once a day, once every two days, onceevery three days, once every four days, once every five days, once everysix days, once a week, once every 10 days, once every two weeks, onceevery three weeks, once a month, once every two months, once every threemonths, once every four months, once every five months, once every sixmonths, once a year, or more. As an alternative or in addition to, acomposition may be delivered to a subject at least once a day, or twicea day, or three times per day, or four times per day, or five times perday, or six times per day, or seven times per day, or eight times perday, or nine times per day, or ten times per day, or eleven times perday, or twelve times per day, or thirteen times per day, or fourteentimes per day, or fifteen times per day, or sixteen times per day, orseventeen times per day, or eighteen times per day, or nineteen timesper day, or twenty times per day, or twenty one times per day, or twentytwo times per day, or twenty three times per day, or twenty four timesper day. As an alternative or in addition to, a composition may bedelivered to a subject as soon as skin begins to epithelialize afterprevious treatment. As an alternative or in addition to, a compositionmay be delivered to a subject as soon as skin has partially epithelizedafter previous treatment. As an alternative or in addition to, acomposition may be delivered to a subject as soon as skin has fullyepithelized after previous treatment.

Dose ranges as described herein provide guidance for the administrationof provided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

A compound or composition, as described herein, can be administered incombination with one or more additional pharmaceutical agents (e.g.,therapeutically and/or prophylactically active agents). The compounds orcompositions can be administered in combination with additionalpharmaceutical agents that improve their activity (e.g., activity (e.g.,potency and/or efficacy) in treating a disease in a subject in needthereof, in preventing a disease in a subject in need thereof, inreducing the risk to develop a disease in a subject in need thereof),improve bioavailability, improve safety, reduce drug resistance, reduceand/or modify metabolism, inhibit excretion, and/or modify distributionin a subject or cell. It will also be appreciated that the therapyemployed may achieve a desired effect for the same disorder, and/or itmay achieve different effects. In certain embodiments, a pharmaceuticalcomposition described herein including a compound described herein andan additional pharmaceutical agent shows a synergistic effect that isabsent in a pharmaceutical composition including one of the compound andthe additional pharmaceutical agent, but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichmay be useful as, e.g., combination therapies. Pharmaceutical agentsinclude therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Pharmaceutical agents includesmall organic molecules such as drug compounds (e.g., compounds approvedfor human or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)).

A pharmaceutical composition of the present disclosure can contain othertopical agents. Topical agents include, but are not limited to, localanesthetics, local analgesics, antimicrobial agents, microbicidalagents, disinfectants, antiseptics, antibiotics, bactericidal agents,bacteriostatic agents, cleansing agents, anti-inflammatory agents,anti-infective agents (e.g., gentian violet), emollients, astringents,anti-acne agents, anti-virals, anti-fungals, fungicides, anti-psoriasisagents, antiparasitics, steroid hormones such as corticosteroids.Examples of topical agents include, but are not limited to, Altabax(retapamulin), Amevive (alefacept), Avita gel, Bactroban cream,benzamycin, erythromycin, botox, cefazolin, dextrose, chloraprep(chlorhexidine gluconate), clindamycin phosphate, condylox (pokofilox),desonate (desonide), differin (adapalene), Dynabac, Elidel, Erivedge(vismodegib), Estrostep, norethindrone acetate, ethinyl estradiol,Extina (ketoconazole), Fiacea (azelaic acid), Finevin, Firazyr(icatibant), Gralise (gabapentin), Horizant (gapabentin enacarbil),hydrochloric acid, hydrogen peroxide, Iamin, Invanz, Iontocaine,IvyBlock, Klaron (sodium sulfacet amide), Lamisil (terbinafinehydrocloride), LaViv (azficel-T), Lustra, Luxiq (betamethasonevalerate), Mentax (butenafine HCl), MetroLotion, Minoxidil, Noritate,nitric acid, Omnicef, Ortho Tri-Cyclee, norgestimate, Picato (ingenolmebutate), Propecia, Protopic (tacrolimus), Condylox (podophotoxin),Regranex (becaplermin), Renova, tratinoin, salagen, sandalwood oil,salicylic acid, Sklice (ivermectin), Stelara (ustkinumab), Sulfamylon,Sylatron (peg interferon alpha-2b), Tazorac, Teflaro (ceftarolinefosamil), Thalomid, Trichloroacetic acid, Tygacil (tigecycline), Veltin(clindamycin phosphate), tretinoin, Veregen (green tea sincatechins),Verdeso (desonide), Vibativ (telavancin), Vibativ (telavancin), Xyzal(levoctirizine dihydrochloride), Yervoy (ipilimumab), Zelboraf(vemurafenib), and Zyclara (imiquimod).

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orcompound described herein and a container (e.g., a vial, ampule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or compound described herein.In some embodiments, the pharmaceutical composition or compounddescribed herein provided in the first container and the secondcontainer are combined to form one unit dosage form.

Thus, in one aspect, provided are kits including a first containercomprising a compound or pharmaceutical composition described herein. Incertain embodiments, the kits are useful for treating a disease (e.g.,infectious disease or skin condition) in a subject in need thereof. Incertain embodiments, the kits are useful for preventing a disease (e.g.,infectious disease or skin condition) in a subject in need thereof. Incertain embodiments, the kits are useful for reducing the risk ofdeveloping or contracting a disease (e.g., infectious disease or skincondition) in a subject in need thereof. In certain embodiments, a kitdescribed herein further includes instructions for using the kit. A kitdescribed herein may also include information as required by aregulatory agency such as the U.S. Food and Drug Administration (FDA).In certain embodiments, the information included in the kits isprescribing information.

In certain embodiments, the active ingredient in a pharmaceuticalcomposition is present in high-purity with respect to the activeingredient (i.e., not taking into account other active ingredients,excipients, carriers, solvents, etc.). In certain embodiments, thepurity is greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,98%, or 99% with respect to the active ingredient. In certainembodiments, the purity is greater than 90% with respect to the activeingredient. In certain embodiments, the purity is greater than 95% withrespect to the active ingredient. In certain embodiments, the purity isgreater than 98% with respect to the active ingredient. In certainembodiments, the purity is greater than 99% with respect to the activeingredient. In certain embodiments, the purity is greater than 99.1%.99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% purity.

Methods of Treatment and Use

Compounds provided herein may have biological activity and therefore canbe useful in the treatment of diseases or conditions (e.g., infectiousdiseases, skin conditions).

Provided herein is a method of treating a disease or condition in asubject, the method comprising administering to the subject an effectiveamount of a compound of Formula (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof. The present invention also provides compounds ofFormula (IV), (V), and (VI), and pharmaceutically acceptable saltsthereof, and pharmaceutical compositions thereof, for use in treatingdiseases and conditions in a subject. The present invention alsoprovides uses of compounds of Formulae (IV), (V), and (VI), orpharmaceutically acceptable salts thereof, and pharmaceuticalcompositions thereof, for the manufacture of medicaments for treatingdiseases or conditions in a subject. In certain embodiments, the diseaseis an infectious disease. In certain embodiments, the conditions is askin condition.

In certain embodiments, the disease is an infectious disease. An“infectious disease” refers to any disease caused by a pathogen (i.e.,pathogenic microorganisms). An infectious disease may be caused bybacteria, viruses, parasites, or fungi. An infectious disease can be amicrobial infection. A “microbial infection” refers to an infection witha microorganism, such as a fungus, bacteria or virus. In certainembodiments, the microbial infection is an infection with a fungus,i.e., a fungal infection. In certain embodiments, the microbialinfection is an infection with a virus, i.e., a viral infection. Incertain embodiments, the microbial infection is an infection with abacteria, i.e., a bacterial infection. Various microbial infectionsinclude, but are not limited to, skin infections, GI infections, urinarytract infections, genito-urinary infections, sepsis, blood infections,and systemic infections. In certain embodiments, the infectious diseaseis a bacterial infection. In certain embodiments, the infectious diseaseis a viral infection. In certain embodiments, the infectious disease isa microbial infection.

In certain embodiments, a compound described herein is useful intreating an infectious disease or skin condition. Examples of infectiousdiseases and skin conditions include, but are not limited to, Acralfibrokeratoma, Acrodermatitus enterpathica, Acrokeratoelastoidosis,Actinic keratosis (solar keratoses), Adenoma sebaceum, Angiokeratoma,Atopic Dermatitis, Basal cell carcinoma, Benign fibrous histiocytomas,Bladder cancer, Bowen's disease, Breast cancer, Buschke-Ollendorffsyndrome, Cervical cancer, Cervical dysplasia, Cherry angiomas,Chondrodermatitis nodularis chronica helicis, Common warts, Cutaneousendometriosis, Cutaneous Leukemia, Cutaneous Lymphoma, Cutaneousmeningioma, Cutaneous myxoma, Darier's disease, Dermal dendrocytehamartoma, dermatofibroma, Dermatofibrosarcoma protuberans, Eccrineangiomatous hamartoma, Ectodermal dysplasia, Epidermal inclusion cysts,Epidermal Naevi, Epithelioid cell histiocytoma, Familial myxovascularfibromas, Fungal skin disease, Granular cell tumor, Glucaonoma syndrome,Genital warts, Ichthyosis, Idiopathic guttate hypomelanosis, Infantileacropustulosis, Infantile fibromatosis, Kaposi's sarcoma, Keloid,Keratoacanthoma, Keratocyst, Knuckle pads, Lentigo, Melanoma,Microvenular hemangioma, Molluscum contagiousum, Morton's neuroma,Multifocal lymphangioendotheliomatosis, Multinucleate cellangiohistocytoma, Multiple cutaneous leiomyomas, Mycosis fungoides,Neuroma cutis, Neurothekeoma, Nevus flammeus, Nevus lipomatosussuperficialis, Pachydermodactyly, Palisaded encapsulated neuroma,Parasitic skin diseases, Pityriasis ruba pilaris, Piloleiomyomas,Plantar warts, Plexiform fibrohistiocytic tumor, Porokeratotic eccrineostial and Dermal duct nevus, Progressive nodular histiocytomaPsoriasis, Porokeratosis, Seborrhoeic dermatitis, Seborrhoeic keratosis,Rhinophyma, Solitary cutaneous leiomyoma, Spider angioma, Targetoidhemosiderotic hemangioma, Squamous cell carcinoma, Tufted angioma,Venous lake, Urticaria pigmentosa, Xanthelasmoidal mastocytosis,Zosteriform metastasis, Benign epidermal cysts, Birthmarks, Calluses,Corns, Eczema, Freckles, Moles, Pigmentation disorders, Drug inducedhyperpigmentation, Dyschromatosis symmetrica hereditaria, Dyschromatosisuniversalis hereditaria, Familial progressive hyperpigmentation,Galli-Galli disease, Hemosiderin hyperpigmentation, Idiopathic guttatehypomelanosis, Iron metallic discoloration, leukoderma, Melasma, Mukamelsyndrome, Necklace of Venus, Nevus anemicus, Nevus depigmentosus,Pallister-Killian syndrome, Phylloid hypomelanosis, Piebaldism,Pigmentatio reticularis faciei et colli, Pilar Cysts, Pityriasis alba,Poikiloderma of Civatte, Poikiloderma vasculare atrophicans,Postinflammatory hyperpigmentation, Progressive macular hypomelanosis,Pruritus, Reticular pigmented anomaly of the flexures, Reticulateacropigmentation of Kitamura, Riehl melanosis, Shah-Waardenburgsyndrome, Shiitake mushroom dermatitis, Tar melanosis, Titanium metallicdiscoloration, Transient neonatal pustular melanosis, Vagabond'sleukomelanoderma, Vasospastic macules, Wende-Bauckus syndrome, X-linkedreticulate pigmentary disorder, Yemenite deaf-blind hypopigmentationsyndrome, Scars, Skin tags, Tattoo removal, and Vitiligo.

DEFINITIONS

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, 2^(nd) Edition, Wiley-VCH Publishers, Inc., New York,1999; and Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd)Edition, Cambridge University Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high-pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY,1962); and Wilen, S. H., Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972). The invention additionally encompasses compounds asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of hydrogen by deuterium ortritium, replacement of ¹⁹F with ¹⁸F, or the replacement of ¹²C with ¹³Cor ¹⁴C are within the scope of the disclosure. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

“Sulfonyl” refers to a group selected from —SO₂N(R^(bb))₂, —SO₂R^(aa),and —SO₂OR^(aa), wherein R^(aa) and R^(bb) are as defined herein.

“Sulfinyl” refers to the group —S(═O)R^(aa), wherein R^(aa) is asdefined herein.

The term “phosphoryl” refers to a group selected from —P(═O)(OR^(cc))₂,—P(═O)(R^(aa))2, and —P(═O)(N(R^(bb))₂)₂, wherein R^(aa), R^(bb), andR^(cc) are as defined herein.

“Sulfonate” refers to a group selected from —OSO₂N(R^(bb))₂,—OSO₂R^(aa), and —OSO₂OR^(aa), wherein R^(aa) and R^(bb) are as definedherein. Examples of sulfonate groups include, but are not limited to,—OSO₂Ph, tosylate (—OSO₂C₆H₄p-CH₃; “OTs”), triflate (—OSO₂CF₃; “OTf”),brosylate (—OSO₂C₆H₄p-Br; “OBs”), nonaflate (—OSO₂(CF₂)₃CF₃; “ONf”),nosylate (—SO₂C₆H₄p-NO₂ or —SO₂C₆H₄o-NO₂; “ONs”), and dansylate (“ODs”).

“Phosphate” refers to a group selected from —O(P═O)(R^(aa))₂,—O(P═O)(OR^(cc))R^(aa), —O(P═O)(OR^(cc))₂, —O(P═O)(NR^(bb))₂ whereinR^(aa), R^(bb), and R^(cc) are as defined herein.

The term “acyl” refers to a group having the general formula—C(═O)R^(X1), —C(═O)OR^(X1), —C(═O)—O—C(═O)R^(X1), —C(═O)SR^(X1),—C(═O)N(R^(X1))₂, —C(═S)R^(X1), —C(═S)N(R^(X1))₂, —C(═S)O(R^(X1)),—C(═S)S(R^(X1)), —C(═NR^(X1))R^(X1), —C(═NR^(X1))OR^(X1),—C(═NR^(X1))SR^(X1), and —C(═NR^(X1))N(R^(X1))₂, wherein R^(X1) ishydrogen, halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —R^(aa), —OR^(cc), or —OR^(bb);or two R^(X1) groups taken together form a 5- to 6-membered heterocyclicring. Exemplary acyl groups include aldehydes (—CHO), carboxylic acids(—CO₂H), ketones, acyl halides, esters, amides, imines, carbonates,carbamates, and ureas.

The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example, “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, thealkyl group is a substituted C₁₋₁₀ alkyl (such as substituted C₁₋₆alkyl, e.g., —CF₃, Bn).

The term “haloalkyl” is a substituted alkyl group, wherein one or moreof the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkylmoiety has 1 to 8 carbon atoms (“C₁₋₈ haloalkyl”). In some embodiments,the haloalkyl moiety has 1 to 6 carbon atoms (“C₁₋₆ haloalkyl”). In someembodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C₁₋₄haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbonatoms (“C₁₋₃ haloalkyl”). In some embodiments, the haloalkyl moiety has1 to 2 carbon atoms (“C₁₋₂ haloalkyl”). Examples of haloalkyl groupsinclude —CHF₂, —CH₂F, —CF₃, —CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂,—CF₂Cl, and the like.

The term “heteroalkyl” refers to an alkyl group, which further includesat least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected fromoxygen, nitrogen, or sulfur within (i.e., inserted between adjacentcarbon atoms of) and/or placed at one or more terminal position(s) ofthe parent chain. In certain embodiments, a heteroalkyl group refers toa saturated group having from 1 to 10 carbon atoms and 1 or moreheteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₉ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 8 carbon atoms and 1 or more heteroatomswithin the parent chain (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 6carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₆ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 3carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 2 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parentchain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstitutedheteroalkyl”) or substituted (a “substituted heteroalkyl”) with one ormore substituents. In certain embodiments, the heteroalkyl group is anunsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkylgroup is a substituted heteroC₁₋₁₀ alkyl.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bondfor which the stereochemistry is not specified

may be an (E)- or (Z)-double bond.

The term “heteroalkenyl” refers to an alkenyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkenylgroup refers to a group having from 2 to 10 carbon atoms, at least onedouble bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkenyl”). In some embodiments, a heteroalkenyl group has2 to 9 carbon atoms at least one double bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 8 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbonatoms, at least one double bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbonatoms, at least one double bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkenyl”).In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, atleast one double bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently unsubstituted (an “unsubstitutedalkynyl”) or substituted (a “substituted alkynyl”) with one or moresubstituents. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

The term “heteroalkynyl” refers to an alkynyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkynylgroup refers to a group having from 2 to 10 carbon atoms, at least onetriple bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkynyl”). In some embodiments, a heteroalkynyl group has2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbonatoms, at least one triple bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbonatoms, at least one triple bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkynyl”).In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, atleast one triple bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

The term “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbonatoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C₅₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can besaturated or can contain one or more carbon-carbon double or triplebonds. “Carbocyclyl” also includes ring systems wherein the carbocyclylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the carbocyclyl ring, andin such instances, the number of carbons continue to designate thenumber of carbons in the carbocyclic ring system. Unless otherwisespecified, each instance of a carbocyclyl group is independentlyunsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ringcarbon atoms (“C₄₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀cycloalkyl”). Examples of C₅₋₆ cycloalkyl groups include cyclopentyl(C₅) and cyclohexyl (C₅). Examples of C₃₋₆ cycloalkyl groups include theaforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl (C₃) andcyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groups include theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇) andcyclooctyl (C₈). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₄ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₄ cycloalkyl.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to14-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a fused, bridged or spiro ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)), and can be saturated or can contain one ormore carbon-carbon double or triple bonds. Heterocyclyl polycyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.In certain embodiments, the heterocyclyl group is a substituted 3-14membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, dioxolanyl,oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl,oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclylgroups containing 1 heteroatom include, without limitation, piperidinyl,tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-memberedheterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary6-membered heterocyclyl groups containing 3 heteroatoms include, withoutlimitation, triazinyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyland thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14π electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certainembodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certainembodiments, the aryl group is a substituted C₆₋₁₄ aryl.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclicor polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14π electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Heteroaryl polycyclicring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the point of attachment is on the heteroaryl ring, and insuch instances, the number of ring members continue to designate thenumber of ring members in the heteroaryl ring system. “Heteroaryl” alsoincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the point of attachment iseither on the aryl or heteroaryl ring, and in such instances, the numberof ring members designates the number of ring members in the fusedpolycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groupswherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include,without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary5-membered heteroaryl groups containing 2 heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing 3heteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4heteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing 1heteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplarytricyclic heteroaryl groups include, without limitation,phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl,phenoxazinyl, and phenazinyl.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl groups are optionally substituted. “Optionallysubstituted” refers to a group which may be substituted or unsubstituted(e.g., “substituted” or “unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” heteroalkyl, “substituted” or“unsubstituted” heteroalkenyl, “substituted” or “unsubstituted”heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl,“substituted” or “unsubstituted” heterocyclyl, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted” means that at least onehydrogen present on a group is replaced with a permissible substituent,e.g., a substituent which upon substitution results in a stablecompound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, and includes any of thesubstituents described herein that results in the formation of a stablecompound. The present invention contemplates any and all suchcombinations in order to arrive at a stable compound. For purposes ofthis invention, heteroatoms such as nitrogen may have hydrogensubstituents and/or any suitable substituent as described herein whichsatisfy the valencies of the heteroatoms and results in the formation ofa stable moiety. The invention is not intended to be limited in anymanner by the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₃, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═R^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂, —NR^(bb)P(═O)(R^(aa))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂,—P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄,—P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻, —OP(OR^(cc))₂,—OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄, —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl,heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is a counterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(aa) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminalR^(dd) substituents can be joined to form ═O or ═S; wherein X⁻ is acounterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆ alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆ alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-10 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(═NH)NH(C₁₋₆ alkyl),—OC(═NH)NH₂, —NHC(═NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂(C₁₋₆ alkyl),—SO₂O(C₁₋₆ alkyl), —OSO₂(C₁₋₆ alkyl), —SO(C₁₋₆ alkyl), —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆ alkyl, heteroC₂₋₆ alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

In certain embodiments, carbon atom substituents include: halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻,—NH₃ ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(═NH)NH(C₁₋₆ alkyl),—OC(═NH)NH₂, —NHC(═NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂(C₁₋₆ alkyl),—SO₂O(C₁₋₆ alkyl), —OSO₂(C₁₋₆ alkyl), —SO(C₁₋₆ alkyl), —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆ alkyl, heteroC₂₋₆ alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively—we are much morelikely to form cationic salts of our mono and di carboxylic acids likeNa, K, NR₄ salts—charged group associated with a positively chargedgroup in order to maintain electronic neutrality. An anionic counterionmay be monovalent (i.e., including one formal negative charge). Ananionic counterion may also be multivalent (i.e., including more thanone formal negative charge), such as divalent or trivalent. Exemplarycounterions include halide ions (e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻,OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻, sulfonate ions (e.g., methansulfonate,trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate,10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonicacid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like),carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate,lactate, tartrate, glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻,PF₆ ⁻, AsF₆ ⁻, SbF₆ ⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄ ⁻, BPh₄ ⁻,Al(OC(CF₃)₃)₄ ⁻, and carborane anions (e.g., CB₁₁H₁₂ ⁻ or(HCB₁₁Me₅Br₆)⁻). Exemplary counterions which may be multivalent includeCO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻. B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻, carboxylate anions(e.g., tartrate, citrate, fumarate, maleate, malate, malonate,gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate,sebacate, salicylate, phthalates, aspartate, glutamate, and the like),and carboranes.

As used herein, use of the phrase “at least one instance” refers to 1,2, 3, 4, or more instances, but also encompasses a range, e.g., forexample, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to3, or from 3 to 4 instances, inclusive.

Any compound provided herein, or used in a method provided herein, canbe provided and/or used as a salt thereof. As used herein, the term“salt” refers to any and all salts, and encompasses pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acids,such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids, such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “leaving group” is given its ordinary meaning in the art ofsynthetic organic chemistry and refers to an atom or a group capable ofbeing displaced by a nucleophile. See, for example, Smith, MarchAdvanced Organic Chemistry 6th ed. (501-502). Examples of suitableleaving groups include, but are not limited to, halogen (such as F, Cl,Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy,alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, andhaloformates. In some cases, the leaving group is a sulfonic acid ester,such as toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate,—OMs), p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS(═O)₂(CF₂)₃CF₃(nonaflate, —ONf), or trifluoromethanesulfonate (triflate, —OTf). Insome cases, the leaving group is a brosylate, such asp-bromobenzenesulfonyloxy. In some cases, the leaving group is anosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may alsobe a phosphineoxide (e.g., formed during a Mitsunobu reaction) or aninternal leaving group such as an epoxide or cyclic sulfate. Othernon-limiting examples of leaving groups are water, ammonia, alcohols,ether moieties, thioether moieties, zinc halides, magnesium moieties,diazonium salts, and copper moieties. Further exemplary leaving groupsinclude, but are not limited to, halo (e.g., chloro, bromo, iodo) andactivated substituted hydroxyl groups (e.g., —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, wherein X⁻,R^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 5^(th) edition, John Wiley & Sons, 2014, incorporated herein byreference.

The term “solvent” refers to a substance that dissolves one or moresolutes, resulting in a solution. A solvent may serve as a medium forany reaction or transformation described herein. The solvent maydissolve one or more reactants or reagents in a reaction mixture. Thesolvent may facilitate the mixing of one or more reagents or reactantsin a reaction mixture. The solvent may also serve to increase ordecrease the rate of a reaction relative to the reaction in a differentsolvent. Solvents can be polar or non-polar, protic or aprotic. Incertain embodiments, a reaction described herein is carried out in anionic liquid. Common organic solvents useful in the methods describedherein include, but are not limited to, acetone, acetonitrile, benzene,benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methylether, carbon disulfide carbon tetrachloride, chlorobenzene,1-chlorobutane, chloroform, cyclohexane, cyclopentane,1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM),N,N-dimethylacetamide N,N-dimethylformamide (DMF),1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane,1,3-dioxane, diethylether, 2-ethoxyethyl ether, ethyl acetate, ethylalcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, hexanes,hexamethylphosphoramide (HMPA), 2-methoxyethanol, 2-methoxyethylacetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone,2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone,dimethylsulfoxide (DMSO), dimethyl sulfone, sulfolane, nitromethane,1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine,tetrachloroethylene, tetrahyrdofuran (THF), 2-methyltetrahydrofuran,toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane,2,2,4-trimethylpentane, trimethylamine, triethylamine,N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, andp-xylene.

The term “catalysis,” “catalyze,” or “catalytic” refers to the increasein rate of a chemical reaction due to the participation of a substancecalled a “catalyst.” In certain embodiments, the amount and nature of acatalyst remains essentially unchanged during a reaction. In certainembodiments, a catalyst is regenerated, or the nature of a catalyst isessentially restored after a reaction. A catalyst may participate inmultiple chemical transformations. The effect of a catalyst may vary dueto the presence of other substances known as inhibitors or poisons(which reduce the catalytic activity) or promoters (which increase theactivity). Catalyzed reactions have lower activation energy(rate-limiting free energy of activation) than the correspondinguncatalyzed reaction, resulting in a higher reaction rate at the sametemperature. Catalysts may affect the reaction environment favorably,bind to the reagents to polarize bonds, form specific intermediates thatare not typically produced by a uncatalyzed reaction, or causedissociation of reagents to reactive forms.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)) or non-human animal. In certainembodiments, the non-human animal is a mammal (e.g., primate (e.g.,cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g.,cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.,commercially relevant bird, such as chicken, duck, goose, or turkey)).In certain embodiments, the non-human animal is a fish, reptile, oramphibian. The non-human animal may be a male or female at any stage ofdevelopment. The non-human animal may be a transgenic animal orgenetically engineered animal. The term “patient” refers to a humansubject in need of treatment of a disease.

The term “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a compound described herein, or a composition thereof, in oron a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen). Treatment may also be continued aftersymptoms have resolved, for example, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response. An effectiveamount of a compound described herein may vary depending on such factorsas the desired biological endpoint, the pharmacokinetics of thecompound, the condition being treated, the mode of administration, andthe age and health of the subject. In certain embodiments, an effectiveamount is a therapeutically effective amount. In certain embodiments, aneffective amount is a prophylactic treatment. In certain embodiments, aneffective amount is the amount of a compound described herein in asingle dose. In certain embodiments, an effective amount is the combinedamounts of a compound described herein in multiple doses.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

The methods provided herein may be applied to the synthesis ofcantharidin, for example, as shown in Scheme 4.

As described herein, studies into the industrial scale preparation ofcantharidin led to the discovery of surprising and unprecedentedDiels-Alder reaction conditions for reacting furan and Compound (2) toyield key the synthetic tetracyclic intermediate, Compound (1).

Starting with the work reported by Dauben in the 1980s (See, e.g., JACS,102, 6893 (1980) and JOC, 50, 2576-2578 (1985)), it was presumed thatthis Diels-Alder cycloaddition would require exotic, highly demandingreaction conditions. This assumption arose from the expected stericcongestion that would be generated in formation of Compound (1).Although not the same molecule, the work of Bruchhausen in 1928demonstrated that dehydrocantharidin spontaneously underwent a retroDiels-Alder reaction to alleviate this congestion. In addition, Dielsand Alder reported that the forward reaction of furan and dimethylmaleic anhydride to form dehydrocantharidin was not possible (see, e.g.,BER. 62, 554-562 (1929)). Recognizing this facile retro Diels-Alderliability, Dauben used exceedingly high pressures (>7 kbar) to force theelectrocyclic addition of Compound (2) to Compound (1) in a volumecontraction-driven process. Subsequently Grieco (see, e.g., JACS, 112,4595-459 (1990)) used highly concentrated ethereal solutions of theLewis acid, lithium perchlorate (5 M), to catalyze the reaction as wellas create a high salt content-driven effect (“high” internal solventpressure) to force adduct (1) to form.

Unfortunately, neither the Dauben nor the Grieco conditions are viablelarge-scale production methods for a commercial product. The super highpressures used in the Dauben protocol or the use of ethereal perchloratesolutions of the Grieco method are both subject to significant explosionrisks which are unacceptable to manufacturers. A second Grieco methodusing lithium trifluoromethanesulfonimide in either diethyl ether oracetone also yielded the desired adduct (1) but at a high reagent cost.More significantly, there was a serious erosion of the favorableexo-endo ratio leading to a much poorer yield of Compound (1).

It was discovered that other Lewis acids could replace the lithium Lewisacids in the Grieco procedure (International Publication No. WO2016/100732, published Jun. 23, 2016, the entire contents of which isincorporated herein by reference). These studies demonstrated that theexo/endo ratios were significantly improved, and the product yields wereviable.

However, it was recently discovered that mixing a solution of the tworeactions in a polar solvent like acetonitrile, NMP, DMPU, and acetonesolvents with modest warming gave a 64% conversion to Compound (1) witha very favorable 84:16 ratio of exo-endo isomers (using NMP). Isolationof the desired product Compound (1) could readily be accomplished simplebasic work-up to remove the starting material for reuse and a simplerecrystallization procedure to remove the minor undesired endo isomer.The isolated yield for this reaction is 58% at 99% purity. The fact thatsuch simple reaction conditions are all that is required for successfulformation of adduct (1) from Compound (2) and furan is totallyunexpected based on 37 years of precedent. The success of these specificDiels-Alder conditions was not predicted for these two substrates andare quite suitable for industrial-scale production of cantharidin.

Compound (5) is a key intermediate in a synthesis of cantharidin.Numerous reports of its synthesis have appeared in the literature butare unworkable (use of cyanide or nitromethane) and/or too expensive forindustrial production of Compound (5). In a process never reportedbefore, intermediate (4) (a compound of Formula (II) wherein X¹ is asulfonate) can be carboxylated with palladium-catalyzed addition ofcarbon monoxide to give the key synthetic intermediate (5). This singlestep process gives a 85% yield of Compound (5) despite the presence ofthe typical palladium catalyst poison, sulfur, in both the startingmaterial and product. The presence of the presumably catalyst toxicsulfur is most likely the reason why this conversion has not beenreported to date.

Experimental Procedures Preparation of[3-(methoxycarbonyl)-4-oxotetrahydro-3-thienyl]lithium

Methyl acrylate (9.16 mL, 102 mmol) is added to a mixture of methylmercaptoacetate (8.42 mL, 94.2 mmol) and piperidine (0.186 mL, 1.88mmol) at room temperature over 30 min. When addition is complete, themixture is stirred at room temperature for 30 min. In a separate flask,lithium (0.654 g, 94.2 mmol) is dissolved in 40 ml of MeOH under N₂. Themethyl acrylate mixture is added to the lithium methoxide solution atroom temperature under N₂ over 1 hr. When addition is complete, themixture is warmed to reflux for 6 hrs. The MeOH is evaporated and theresulting thick oil is taken up in 30 ml of ice cold water. Theresulting mixture is stirred with ice bath cooling for 1 hr. The solidthat forms is collected by filtration and dried with a N₂ press for 2hrs. The solid is suspended in MTBE (20 ml, 2 vol) and stirred at roomtemperature for 2 hrs. The solid is collected by filtration and driedwith a N₂ press at room temperature for 2 hrs to give[3-(methoxycarbonyl)-4-oxotetrahydro-3-thienyl]lithium (11.0 g;Yield=70.3%) as a light yellow solid.

Preparation of methyl 4-oxotetrahydrothiophene-3-carboxylate

[3-(Methoxycarbonyl)-4-oxotetrahydro-3-thienyl]lithium (17.7 g, 106mmol) is suspended in 100 mL of water and the suspension was acidifiedto pH ˜5 by addition of 1.0N HCl. The resulting mixture is extractedwith 3×50 ml of CH₂Cl₂. The combined CH₂Cl₂ layers are dried over Na₂SO₄and evaporated to give methyl 4-oxotetrahydrothiophene-3-carboxylate (14g; Yield=82%) as a light yellow oil.

Preparation of methyl4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrothiophene-3-carboxylate

A solution of methyl 4-oxotetrahydrothiophene-3-carboxylate (62.0 g, 387mmol), methylene chloride (310 mL, 4800 mmol) (5 volumes), andN,N-diisopropylethylamine (74.2 mL, 426 mmol) is cooled to −30° C. underN₂. To the solution is added trifluoromethanesulfonic anhydride (68.4mL, 406 mmol) at a rate that maintains the reaction mixture at or below−20° C. When addition is complete, the mixture is stirred at −30° C. for½ hour at which point TLC in CH₂Cl₂ showed no starting materialremained. The reaction was quenched by addition of 300 ml of water andthe layers were separated. The CH₂Cl₂ layer was extracted with 200 ml ofwater and dried over Na₂SO₄. Evaporation of the solvent gave 172 g of adark oil. The oil was taken up in 200 ml of 1:1 CH₂Cl₂/hexane andadsorbed onto a silica gel pad (258 g, 1.5 weights). The pad was elutedwith 3 L of 1:1 CH₂Cl₂/hexane. Evaporation of the filtrate and dryingunder high vacuum at room temperature overnight gave 101 g of methyl4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrothiophene-3-carboxylate(101 g; Yield=89%) as a light yellow oil.

Preparation of dimethyl 2,5-dihydrothiophene-3,4-dicarboxylate

An oil bath was pre-heated to 50° C. A mixture of methyl4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrothiophene-3-carboxylate(15.58 g, 53.31 mmol), tris(dibenzylideneacetone)dipalladium(0) (742 mg,0.810 mmol), and 1,1′-Bis(diphenylphosphino)ferrocene (888 mg, 1.60mmol) were suspended in methanol (10.2 mL, 252 mmol) and DMF (5.1 mL, 66mmol) in a 100 mL pressure tube fitted with a pressure gauge. The tubewas pressurized with 40 psi of CO and the CO was allowed to vent. Thepurging process was repeated once more and then the reaction waspressurized again with 40 psi of CO. The tube was placed in thepre-heated oil bath and was stirred for 24 h. After 24 h, HPLC analysisshowed complete conversion of the starting material. The reactionmixture was transferred to a round-bottom flask and concentrated invacuo to remove methanol. The thick residual mixture was filteredthrough a pad of Magnesol (60 g) and the filter cake was washed withTBME (400 mL). The filtrate was concentrated in vacuo to afford theproduct (13.05 g; Yield=84.73%; Purity=70%; as an orange oil). If therate of the reaction is slow, additional Pd₂(dba)₃ and dppf can beadded. ¹H NMR was acquired in CDCl₃ w/p-xylene as an internal standard.On a 3.0 g scale, this procedure gave an 85% yield at 72% purity. On a19.4 g scale, the concentrated reaction mixture was filtered through aglass frit with a layer of Magnesol (top layer, 40 g) and silica gel(bottom layer, 30 g) and the filter cake was washed with 20%EtOAc/hexanes (500 mL). The filtrate was concentrated in vacuo to afford9.3 g of the product as a pale yellow oil (69% yield, 103% pure byquantitative NMR as described above).

Preparation of 2,5-dihydrothiophene-3,4-dicarboxylic acid

To a solution of dimethyl 2,5-dihydrothiophene-3,4-dicarboxylate (13.05g, 45.17 mmol; Purity=70%) in THF (60 mL) was added 6 M sodium hydroxidein water (40 mL, 250.0 mmol). After an induction period (˜10 min), therewas an apparent exotherm (not measured). After 2.5 h, HPLC analysisshowed complete conversion to diacid. The reaction mixture wasconcentrated in vacuo to remove THF. The mixture was diluted with TBME(100 mL),the layers were partitioned in a separatory funnel, and theorganic layer was set aside. The aqueous layer was returned to thereaction flask and acidified with 2 M HCl (45 mL) to pH 1. A precipitateformed and was filtered (0.9 g). ¹H NMR analysis of the precipitate wasconsistent with the diacid. The aqueous layer was extracted with EtOAc(3×100 mL). Combined extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the product (7.36 g; Yield=76.7%;Purity=82%) as a light orange solid. ¹H NMR was acquired in DMSO-d6w/p-xylene as an internal standard. When the reaction was run on asmaller scale (2.31 g; 72% purity), it afforded 1.2 g of the titlecompound at 92% purity (76% yield) as a tan-colored solid. When thereaction is run by adding diester to a NaOH solution, the exotherm ismore easily controlled, but this led to a lower isolated yield (˜50%)and the isolated product was less pure (60-75%).

Preparation of 4,6-dihydro-1H,3H-thieno[3,4-c]furan-1,3-dione

A suspension of 2,5-dihydrothiophene-3,4-dicarboxylic acid (1.22 g, 7.00mmol) in toluene (4.9 mL, 46 mmol) and acetyl chloride (1.20 mL, 16.8mmol) was heated to reflux for 4 h. The mixture was allowed to cool tort and was concentrated in vacuo. The residue was suspended in acetone(10 mL) and was filtered through a pad of Magnesol (5 wts). The filtercake was washed with acetone (200 mL) and the filtrate was concentratedin vacuo to afford the product (0.801 g; Yield=70.3%; Purity=96%) as atan solid.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein.

It is also noted that the terms “comprising” and “containing” areintended to be open and permits the inclusion of additional elements orsteps. Where ranges are given, endpoints are included. Furthermore,unless otherwise indicated or otherwise evident from the context andunderstanding of one of ordinary skill in the art, values that areexpressed as ranges can assume any specific value or sub-range withinthe stated ranges in different embodiments of the invention, to thetenth of the unit of the lower limit of the range, unless the contextclearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A method of preparing Compound (1):

the method comprising reacting Compound (2):

with furan; wherein the reaction is carried out in the absence of aLewis acid; and wherein the reaction is carried out at aroundatmospheric pressure.
 2. The method of claim 1, wherein the reaction iscarried out in the absence of added acid. 3-6. (canceled)
 7. The methodof claim 1, wherein the reaction is carried out in the absence of aBrønsted acid.
 8. The method of claim 1, wherein the reaction is carriedout at a pressure of approximately 1 atm.
 9. The method of claim 1,wherein the reaction is carried out in the absence of added acid and inthe absence of increased pressure.
 10. The method of claim 1, whereinthe reaction is carried out in a solvent. 11-16. (canceled)
 17. Themethod of claim 1, wherein the reaction is carried out in the absence ofsolvent. 18-21. (canceled)
 22. The method of claim 1, wherein thereaction is carried out at a temperature below 100° C.
 23. The method ofclaim 22, wherein the reaction is carried out at approximately roomtemperature. 24-29. (canceled)
 30. The method of claim 1, wherein furanis present in greater than 1 equivalent relative to the amount ofCompound (2) in the reaction mixture.
 31. The method of claim 30,wherein the ratio of Compound (2) to furan in the reaction mixture isfrom 1:4 to 1:5.
 32. (canceled)
 33. The method of claim 1, wherein theCompound (1) is formed in exo/endo ratio of about 70:30 to 99:1. 34-36.(canceled)
 37. The method of claim 33, wherein the exo/endo ratio isabout 98:2.
 38. The method of claim 1, wherein Compound (1) is isolatedin greater than 50% yield. 39-46. (canceled)
 47. The method of claim 1further comprising a step of hydrogenating Compound (1) to yieldCompound (3):

48-49. (canceled)
 50. The method of claim 47 further comprising a stepof reducing Compound (3):

to yield cantharidin:

51-53. (canceled)
 54. A method of preparing a compound of Formula (IV):

the method comprising reacting a compound of Formula (III):

in the presence of furan, wherein: n is 0, 1, 2, 3, 4, or 5; eachinstance of R³ is independently hydrogen, halogen, —CN, —NO₂, —N₃,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfinyl, —OR^(O),—N(R^(N))₂, or —SR^(S); each instance of R^(O) is independentlyhydrogen, optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted acyl, oran oxygen protecting group; each instance of R^(N) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted acyl, or anitrogen protecting group; or optionally two R^(N) on the same nitrogenare joined together with the intervening atoms to form optionallysubstituted heterocyclyl or optionally substituted heteroaryl; and eachinstance of R^(S) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, or a sulfur protecting group. 55-98.(canceled)
 99. A method of preparing a compound of Formula (I):

the method comprising reacting a compound of Formula (II):

in the presence of palladium, carbon monoxide, and a reagent of theformula R²OH; wherein: X¹ is halogen, optionally substituted sulfonate,or optionally substituted phosphonate; R¹ and R² are independentlyoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, or an oxygen protecting group. 100-134.(canceled)
 135. A compound of Formula (II):

wherein: X¹ is halogen, optionally substituted sulfonate, or optionallysubstituted phosphonate; R¹ is optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, or anoxygen protecting group. 136-142. (canceled)
 143. The compound of claim135, wherein the compound is:

144-155. (canceled)